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Article

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Nitrones with Strained Allenes
Luis R. Domingo, Mar Ríos-Gutiérrez and Patricia Pérez


The [3+2] cycloaddition (32CA) reaction of C-phenyl-N-ter-butylnitrone with 1,2-cyclohexadiene (CHDE), a strained allene, has been studied within the Molecular Electron Density Theory (MEDT). This non-polar 32CA reaction, which takes place through a non-concerted two-stage one-step mechanism, proceeds with a moderate activation energy of 8.5 kcal·mol-1, and presents low stereo- and regioselectivities. The reaction begins by the creation of a pseudoradical center at the central carbon of the strained allene with a relatively low energy cost, 8.3 kcal·mol-1, which immediately promotes the first C-C single bond formation. This scenario is completely different from that of the 32CA reaction involving the simplest allene, which present an activation energy of 24.5 kcal·mol-1. The strain present in CHDE changes its reactivity to that characteristic of radical species. Consequently, the radical reactivity type of the strained allene is responsible for the feasibility of this 32CA reaction, and not its geometry distortion such as has been recently proposed (J. Am. Chem. Soc., 2016, 138, 2512).


The present MEDT study emphasises that the proposed Distortion Interaction Energy Model (DIEM), which is physically meaningless, as well as the obsolete Frontier Molecular Orbital (FMO) theory, are not suitable for the study of the reactivity in organic chemistry, while MEDT provides a profound rationalisation of reactivity based on the only physical observable, the electron density.
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Article

A Molecular Electron Density Theory Study of the Reactivity of Azomethine Imine in [3+2] Cycloaddition Reactions

Luis R. Domingo and Mar Ríos-Gutiérrez



The electronic structure and the participation of the simplest azomethine imine (AI) in [3+2] cycloaddition (32CA) reactions have been analysed within the  Molecular Electron Density Theory (MEDT) using DFT calculations at the MPWB1K/6-311G(d) level. Topological analysis of the electron localisation function reveals that AI has a pseudoradical structure, while the conceptual DFT reactivity indices characterises this TAC as a moderate electrophile and a good nucleophile. The non-polar 32CA reaction of AI with ethylene takes place through a one-step mechanism with moderate activation energy, 7.7 kcal·mol-1. A bonding evolution theory study indicates that this reaction takes place through a non-concerted [2n+2t] mechanism in which the C-C bond formation is clearly anticipated prior to the C-N one. On the other hand, the polar 32CA reaction of AI with dicyanoethylene takes place through a two-stage one-step mechanism. Now, the activation energy is only 0.4 kcal·mol-1, in complete agreement with the high polar character of the more favourable regioisomeric transition state structure. The current MEDT study makes it possible to extend Domingo’s classification of 32CA reactions to a new pmr-type of reactivity.

Pseudoradical structure of the simplest azomethine imine


Electronic structure of TACs and the proposed reactivity types in the non-polar 32CA reactions towards ethylene 


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Article

Understanding the domino reactions between 1-diazopropan-2-one and 1,1-dinitroethylene. A molecular electron density theory study of the [3+2] cycloaddition reactions of diazoalkanes with electron-deficient ethylenes

Luis R. Domingo, Mar Ríos-Gutiérrez, and Saeedreza Emamian


The reaction between 1-diazopropan-2-one and 1,1-dinitroethylene has been studied using the Molecular Electron Density Theory (MEDT) at the B3LYP/6-31G(d,p) computational level. This reaction comprises two domino processes initialised by a common [3 + 2] cycloaddition (32CA) reaction yielding a 1-pyrazoline, which participates in two competitive reaction channels. Along channel I, 1-pyrazoline firstly tautomerises to a 2-pyrazoline, which by a proton abstraction and spontaneous loss of nitrite anion yields the final pyrazole, while along channel II, the thermal extrusion of the nitrogen molecule in 1-pyrazoline gives a very reactive diradical intermediate which quickly yields the final gemdinitrocyclopro- pane. Analysis of the conceptual DFT reactivity indices permits an explanation of the participation of 1-diazopropan-2-one in polar 32CA reactions. A Bonding Evolution Theory (BET) study along the more favourable regioisomeric reaction path associated to the 32CA reaction allows an explanation of its molecular mechanism. The present MEDT study sheds light on these complex domino reactions as well as on the participation of diazoalkanes in polar 32CA reactions towards strong electrophilic ethylenes via a two-stage one-step mechanism.

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Article

How does the Global Electron Density Transfer Diminish Activation Energies in Polar Cycloaddition Reactions? A Molecular Electron Density Theory Study  

Luis R. Domingo, Mar Ríos-Gutiérrez, and Patricia Pérez

Tetrahedron 201773, 1718-1724

The key role of the Global Electron Density Transfer (GEDT) in polar cycloaddition reactions is analysed within the Molecular Electron Density Theory (MEDT) using Density Functional Theory (DFT) calculations at the MPWB1K/6-311G(d) computational level. A comparative MEDT study of the non-polar Diels-Alder reaction between cyclopentadiene (Cp) and ethylene and the polar Diels-Alder reaction between Cp and tetracyanoethylene makes it possible establishing that the GEDT taking place going towards the transition state structures favours the bonding changes required for the formation of the new C-C single bonds along polar cycloaddition reactions. Analysis of the reactivity indices defined within the conceptual DFT at the ground state of the reagents permits to predict the reactivity of organic molecules in polar reactions.

The GEDT taking place along a polar reaction favours the bonding changes required for the formation of the new C-C single bonds 
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Article

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of Nitrones with Ketenes

Mar Ríos-Gutiérrez, Andrea Darù, Tomás Tejero, Luis R. Domingo and Pedro Merino

Org. Biomol. Chem. 2017, 15, 1618–1627

The [3+2] cycloaddition (32CA) reaction between nitrones and ketenes has been studied within the Molecular Electron Density Theory (MEDT) at the Density Functional Theory (DFT) MPWB1K/6-311G(d,p) computational level. Analysis of the conceptual DFT reactivity indices allows explaining the reactivity, and the chemo- and regioselectivity experimentally observed. The particular mechanism of this 32CA reaction involving low electrophilic ketenes has been elucidated by using a bonding evolution theory (BET) study. It is determined that this reaction takes place in one kinetic step only but in a non-concerted manner since two stages are clearly identified. Indeed, the formation of the second C-O bond begins when the first O-C bond is already formed. The study has also been applied to predict the reactivity of nitrones with high electrophilic ketenes. Interestingly, the study predicts a switch to a two-step mechanism due to the higher polar character of this zw-type 32CA reaction. In both cases, BET supports the non-concerted nature of the 32CA reactions between nitrones and ketenes.


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Article
The second citation to MEDT

A new model for C-C bond formation processes derived from the Molecular Electron Density Theory in the study of the mechanism of [3+2] cycloaddition reactions of carbenoid nitrile ylides with electron-deficient ethylenes.
Luis R. Domingo, Mar Ríos-Gutiérrez and Patricia Pérez

Tetrahedron 201672, 1524-1532.


The [3+2] cycloaddition (32CA) reactions of the nitrile ylide (NY) with ethylene and with dicyanoethylene (DCE) have been studied using the Molecular Electron Density Theory through DFT calculations at the MPWB1K/6-31G(d) level. The analysis of the electronic structure of NY indicates that it presents a carbenoid structure with a sp2 lone pair at the carbon atom. While the 32CA reaction with ethylene presents a low activation energy, 6.1 kcal·mol-1, the transition state structure associated with the 32CA reaction of NY with DCE is located 7.5 kcal·mol-1 below the reagents, the reaction being completely regioselective. The topological analysis of the Electron Localisation Function (ELF) along the reaction path permits to establish a new model for the C-C bond formation characterised by the donation of the electron-density of a sp2 carbon lone pair to the most electrophilic carbon atom of an electron-deficient ethylene. The carbenoid character of NY allows to introduce a new type of 32CA reaction, carbenoid type (cb-type).








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Article
Aromaticity in Pericyclic Transition State Structures? A Critical Rationalisation Based on the Topological Analysis of Electron Density.

L. R. Domingo, M. Ríos-Gutiérrez, E. Chamorro and P. Pérez

ChemistrySelect 20161, 6026 - 6039.

The nature of the electron delocalisation pattern within a cyclic structure, i.e. the aromatic character, is examined for six-membered pseudocyclic transition state structures (TSs) involved in five representative examples of so-called pericyclic reactions. Results of the electron localisation function (ELF) and the quantum theory of atoms in molecules (QTAIM) analyses of the electron density evidence that in four of the cases, at least one pair of atoms are not bound at the TS configuration, thus precluding a possible cyclic conjugation. These findings make it possible to rule out the aromatic character of these TSs. High values of the synchronicity Sy index at the TSs contrast with the bonding changes evidenced by ELF topological analysis. The magnitude of the nucleus independent chemical shift (NICS) computed for the five TSs becomes much more negative than that of the reference system, benzene, with no obvious relation to the strong evidence of the pattern of delocalisation revealed by the topological analysis of ELF and QTAIM for each TS. The topology of the anisotropy of current induced density (ACID) at each TS reveals the actual existence of strong non-symmetrical patterns of electron delocalisation of the five TSs.



Pseudocyclic reactions studied

ELF

QTAIM

Representation of the total electron density, ELF basins, ELF attractor positions and colour-filled maps of the ELF of TS1TS5. Basin populations are given in e, average number of electrons. Red line represents a non-bonding region between two atoms. 

Representations of the contour line maps of the Laplacian of the electron density of the five TSs on the molecular plane defined by the atoms involved in the C-C and C-H bond formation. Cps with Ñ2rcp < 0 are coloured in blue colour and cps with Ñ2rcp > 0 are coloured in red.

Both ELF and QTAIM topological analyses of the electron density of the pseudocyclic TS1, TS2 and TS5 indicate that, at least, two continuous carbon atoms are non-covalently bound. These findings make it possible to reject, according to Hückel's definition of aromaticity, an aromatic character of the corresponding TSs. 

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Article

Electrophilic activation of CO2 in cycloaddition reactions towards a nucleophilic carbenoid intermediate: new defying insights from the Molecular Electron Density Theory.



Luis R. Domingo, Mar Ríos-Gutierrez, Eduardo Chamorro and Patricia Pérez

Theor. Chem. Acc. (2016).


The electrophilic activation of the two C=O double bonds of CO2 in the cycloaddition reactions involved in the domino reaction between methyl isocyanide, acetylenedicarboxylate and CO2 yielding a spiro-compound has been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. The approaching mode of the carbonyl groups of CO2 and lactone to the high nucleophilic carbenoid intermediate generated in the first reaction of this domino process promotes the C-C bond formation and the subsequent ring closure. MEDT analysis of cycloaddition reactions involved in this domino process enables to understand the molecular mechanism of these [2n+2n] cycloadditions, which is different from the previously proposed [4p+2p] cycloadditions derived from the Frontier Molecular Orbital (FMO) theory.




Special approach of CO2 and lactone to the high nucleophilic carbenoid intermediate IN.

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[3+2] cycloaddition reactions

A useful classification for [3+2] cycloaddition reactions

Based on the MEDT study of the relationship between the structure of the Three-Atoms-Components (TACs) involved in [3+2] cycloaddition (32CA) reactions and their reactivity, these reactions are classified in:

Pseudodiradical-type(pr-type) 32CA reactions. These reactions are chacaterised by taking place with a very low activation energy and a very low global electron density transfer (GEDT) at the transition state structure (TS).

Carbenoid-type (cb-type) 32CA reactions. The feasibility of these reactions depends on their polar character,i.e. the nucleophilic character of the carbenoid TAC and the electrophilic character of the ethylene derivative.

Zwitterionic-type (zw-type) 32CA reactions. Like cb-type reactions, the feasibility of these reactions depends on their polar character,i.e. the nucleophilic character of the zwitterionic TAC and the electrophilic character of the ethylene derivative or vice versa.

L. R. Domingo, S. R. Emamian,Tetrahedron 2014, 70, 1267-1273.

L. R. Domingo, M. Ríos-Gutiérrez, P. Pérez, Tetrahedron 2016, 72, 1524-1532.


32CA reactions

32CA reactions

article

Non-classical CH···O hydrogen-bond determining the regio- and stereoselectivity in the [3 + 2] cycloaddition reaction of (Z)-C-phenyl-N-methylnitrone with dimethyl 2-benzylidenecyclopropane-1,1-dicarboxylate. A topological electron-density study.

Abdelmalek Khorief Nacereddine, Chafia Sobhi, Abdelhafid Djerourou,

Mar Ríos Gutiérrez and Luis R. Domingo

RSC Adv., 2015, 5, 99299–99311

The presence of the two CO2Me groups in the cyclopropane ring has a remarkable effect on selectivities favouring the ortho/endo path, in good agreement with the experimental data. Non-covalent interaction (NCI) analysis of the most favourable ortho/endo transition state structure reveals that the formation of a non-classical CH···O hydrogen-bond involving the nitrone C–H hydrogen is responsible for the selectivity experimentally found in this non-polar zw-type 32CA reaction. An electron localisation function (ELF) topological analysis along the most favourble reaction path allows explaining the formation of the C–C and O–C bonds through a non-concerted two-stage one-step mechanism.

Analysis NCI

Analysis NCI

Diels-Alderases: Reality or Fantasy?

Diels-Alderase Catalysing the Cyclisation Step in the Biosynthesis ofSpinosyn A: Reality or Fantasy?

Luis R. Domingo, Jose A. Sáez, Lydia Rhyman and Ponnadurai Ramasami.

Emerging Trends in Computational Biology, Bioinformatics, and Systems Biology - Algorithms and Software Tools, Q.-N, Tran and H. R. Arabnia eds, Publisher: Elsevier/MK. pp 169-201 (2015)

The conversion of putative macrocyclic lactone into the tricyclic compound, as a key step in the biosynthesis of spinosyn A reported by Kim et al. (Nature, 2011, 473, 109), has been theoretically investigated using DFT methods. The relatively low activation free energy computed for the cyclisation process of the actual macrocyclic lactone, 21.0 kcal/mol, furnishes a rationalisation for a spontaneous (i.e. non-enzymatically catalysed) cyclisation process in the biosynthesis of spinosyn A. A geometrical analysis of putative macrocyclic lactone indicates that a slight strain on the lactone at the active site of the SpnF gene could decrease the activation free energy to ca. 16 kcal/mol. This non-specific participation of the enzyme, which accounts for the relatively low 500-fold acceleration that Kim et al. found in this gene, rules out the participation a specific Diels-Alderase.

Scheme

Scheme

Article

A DFT Study of the Mechanism of Brønsted Acid Catalysed Povarov Reactions.

Mar Ríos-Gutiérrez,Hatem Layeb, Luis R Domingo

Tetrahedron 2015, 71, 9339-9345

The molecular mechanism of the Brønsted acid (BA) catalysed Povarov reaction of N-phenyl-C-methoxycarbonyl imine with a methylene-cyclopropane (MCP) has been investigated using DFT methods at theMPWB1K/6-31G(d) level. This BA catalysed Povarov reaction is a domino process initialised by the formation of acationic intermediate which experiences a quick intramolecular Friedel-Craft reaction yielding the final tetrahydroquinoline.Protonation of imine nitrogen atom notably increases the electrophilicity of the corresponding species, accelerating the reaction through ionic processes. Analysis of the Parr functions in the initial nucleophilic attack of MCP to the protonated imine allows explaining the total regioselectivity experimentally observed. An electron localisation function quantum topological analysis of the bonding changes along the BA catalysed Povarov reaction permits a complete characterisation of the molecular mechanism.

Scheme

Scheme

Article

A Bonding Evolution Theory Study of the Mechanism of [3+2] Cycloaddition Reactions of Nitrones with Electron-Deficient Ethylenes

Mar Ríos-Gutiérrez, Patricia Pérez and Luis R. Domingo

RSC Adv. 2015, 15, 58464-58477

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The mechanism of zw-type [3+2] cycloaddition (32CA) reactions of nitrones with electron-deficient (ED) ethylenes has been studied using density functional theory (DFT) methods at the MPWB1K/6-31G(d) level of theory. An exploration of the potential energy surfaces associated with the four competitive reactive channels of the 32CA reaction between C-phenyl-N-methyl nitrone and acrolein indicates that the cycloaddition reaction takes place through a one-step mechanism. This cycloaddition reaction presents a moderate metaregioselectivity and a complete endo stereoselectivity, which is diminished in dichloromethane. Analysis of the DFT reactivity indices of the reagents allows explaining the participation of nucleophilic nitrones in zw-type 32CA reactions towards ED ethylenes. A bonding evolution theory (BET) study of the two endo regioisomeric reactive channels allows establishing the molecular mechanism of these relevant 32CA reactions. Both regioisomeric channels topologically take place along eight differentiated phases. While the formation of the C-C single bond follows Domingo’s recently proposed model, the formation of the O-C single bond takes place at the short distance of 1.6 Å through the donation of some electron density of the oxygen lone pairs of the nitrone to the b-conjugated carbon atom of acrolein. BET supports the non-concerted nature of these zw-type32CA reactions and makes it possible to reject the pericyclic mechanism proposed for them.

Scheme

Scheme

Article

Unraveling the Mechanism of the Ketene-Imine Staudinger Reaction. An ELF Quantum Topological Analysis

Luis R. Domingo, Mar Ríos-Gutiérrez, José A. Sáez

RSC Adv. 2015, 5, 37119–37129

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The mechanism of the ketene-imine Staudinger reaction (KI-S) between t-butyl-cyano ketene and N-phenyl phenylimine has been studied using DFT methods at the MPWB1K/6-311G(d) computational level. The reaction takes place through a two-step mechanism: i) the first step is the nucleophilic attack of the imine nitrogen lone pair on the central carbon of the ketene yielding a zwitterionic (ZW) intermediate; ii) the second step, which is the rate- and stereoselectivity-determining step, is a ring-closure process achieved by a nucleophilic attack of the terminal carbon atom of the ketene on the imine carbon atom. Due to the unfeasibility of a cis/trans and an E/Z stereoisomerisation at the ZW intermediates, trans and cis b-lactams are formed along the endo and exo stereoisomeric channels, respectively. An electron localisation function (ELF) quantum topological analysis of the bonding changes along the KI-S reaction permits a complete characterisation of the mechanism. The first step is associated with the formation of the N1-C4 single bond along the nucleophilic attack of imine nitrogen lone pair on the central carbon of ketene, while the second step is associated with a ring-closure process achieved by the C-to-C coupling of the C2 and C3 pseudoradical centers generated in the previous phases. The present theoretical study makes it possible to reject those analyses based on the FMO theory, in which HOMO/LUMO interactions along the nucleophilic attack of the imines on the ketenes and a feasible torquoelectronic effect along the conrotatory ring-closure step control the cis/trans stereoselectivity in the formation of b-lactams.

Staundinger reaction

Staundinger reaction

ARTICLE

A DFT Study of the Inter- and Intramolecular Aryne Ene Reactions

Eur. J. Org. Chem. 2826–2834 (2015)

The molecular mechanism of the inter- and intramolecular aryne ene reactions has been theoretically studied using DFT methods at the MPWB1K/6-311G(d,p) level. These reactions take place through a one-step mechanism via nearly asynchronous TSs in which the C-C single bond formation is slightly more advanced than the hydrogen transfer process. These ene reactions show very low activation enthalpies (< 1kcal/mol) being strongly exothermic by more than 73 kcal/mol. An electron localisation function (ELF) topological analysis of the changes of electron density along these ene reactions indicates that the bonding changes are non-concerted. ELF topological analysis of the electron density in the C1-C2 bonding region of benzyne points out that the 1,2-pseudodiradical vinyl structure more than a CC triple bond one is responsible for the very high reactivity of these species.

ENE REACTION OF ARYNES

ENE REACTION OF ARYNES

Article

A DFT Study of the Ionic [2+2] Cycloaddition Reactions of Keteniminium Cations with Terminal Acetylenes.

Luis R. Domingo, Mar Ríos-Gutiérrez and Patricia Pérez

Tetrahedron 2015, 71, 2421-2427,

The molecular mechanism of the ionic [2+2] cycloaddition (I-22CA) reactions of a keteniminium cation (KC) with acetylene and propyne has been investigated using DFT methods at the MPWB1K/6-311G(d,p) level. These I-22CA reactions take place via a two-step mechanism. The first step is the nucleophilic attack of these alkynes on the central carbon of KC, yielding cyclopropene intermediates, while the second step corresponds to the conversion of these intermediates into more stable cyclobuteniminium cations (CCs). The first step is the rate-determining step, while the second step is responsible for the formation of the two regioisomeric CCs experimentally observed in the reaction with propyne. Analysis of the DFT reactivity indices indicates that the strong electrophilic character of KC accounts for the feasibility of these I-22CA reactions. An ELF topological analysis of the changes of the electron density along the IRCs of the two reaction steps allows the molecular mechanism of these I-22CA reactions to be established.

ionic [2+2] cycloaddition reactions

ionic [2+2] cycloaddition reactions

Article

A Mechanistic Study of the Participation of Azomethine Ylides and Carbonyl Ylides in [3+2] Cycloaddition Reactions.

Tetrahedron 2015, 71, 1050-1057.

The participation of azomethine ylides (AYs) and carbonyl ylides (CYs) in [3+2] cycloaddition (32CA) reactions has been analysed at the DFT B3LYP/6-31G(d) level. The asymmetric substitution breaks the pseudodiradical character of the simplest three-atom-components (TACs), modifying their electrophilic and nucleophilic behaviours. These TACs react quickly towards electrophilic nitroethylene. However, while the reaction with AY takes place via a zw-type mechanism, the reaction with CY appears to take place via a pr-type mechanism. A different behaviour is found in the reactivity towards the nucleophilic methyl vinyl ether. While AY presents a high activation energy, CY presents a high reactivity via a pr-type mechanism. These reactions are completely regioselective, displaying exo stereoselectivity. The present study makes it possible to establish that the substitution provokes a different reactivity pattern in these TACs; while in CYs does not substantially modify their pr-type reactivity, AYs only participate in zw-type 32CA reactions towards electrophilic ethylenes.

32CA Reactions

32CA Reactions

Erroneous Concepts in Organic Chemistry

Why Houk's distortion/interaction energy model is an erroneous reactivity model.

Houk's distortion/interaction [J. Am. Chem. Soc., 2007, 129, 10646] model based on the fragmentation of the TS geometry is conceptually erroneous as both molecular energy and geometry depend on the electron-density, which physically is not divisible. Since the computed E*distorsion (E*d) is always higher than the real one, this model always underestimate the interaction energy E*int, which is the factor responsible for the feasibility of an organic reaction.

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ARTICLE

WHY DIELS-ALDER REACTIONS ARE NON-CONCERTED PROCESSES

J. Chil. Chem. Soc., 2014, 59, 2615.2618

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In this short manuscript, why Diels-Alder reactions are non-concerted processes is analyzed. Recent ELF topological analyses of cycloaddition mechanisms have evidenced that bonding changes take place along a sequential bond-breaking/bond-formation process. The most relevant topological behavior along these reactions is the formation of the new C-C single bonds by coupling of two pseudoradical carbons. Formation of these pseudoradical carbons is attained through the depopulation of the C-C double bonds present in the diene and ethylene. This demand provokes the rupture of the C-C double bonds at the begging of the reaction, and before the formation of the new C-C single bonds. Consequently, the C=C breaking and the C-C bond formation processes are non-concerted processes.

The point IRC-12 of the intermolecular DA reaction of 1-(hex-5-enyl)cyclohexa-1,3-diene shows that while the formation of the C1-C5 bond has begun, see the presence of the V(C1,C5) disynaptic basin, the formation of the C4-C6 bond has not started; see the presence of the V(C4) and V(C5) monosynaptic basins. On the other hand, formation of C2-C3 double bond takes place at the end of the reaction.

ELF IMDA reaction

ELF IMDA reaction

Article

Understanding the selectivity in the formation of d-lactams vs b-lactams in the Staudinger reactions of chloro-cyan-ketene with unsaturated imines. An DFT study.

RSC Adv. 2014, 4, 58559

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The reactions of chloro-cyan-ketene with two phenyl substituted unsaturated imines yielding b- or d-lactams have been investigated using DFT methods at the MPWB1K/6-311G(d,p) level in diethyl ether. The reactions are initialised by the nucleophilic attack of the unsaturated imines on the ketene with formation of zwitterionic intermediates. The subsequent C-C single bond formation at the imine carbon or at the b-conjugated position enables the formation of b- or d-lactams. Analysis of the energies involved in the two competitive channels explains the selectivity experimentally observed; in the absence of any steric hindrance, formation d-lactams is favoured over the formation of b-lactams. ELF topological analysis allows explaining the bonding changes along the two competitive channels. While formation of the N-C bond takes place by participation of the nitrogen lone pair, formation of the C-C bonds takes place through a retrodonation process involving the C-C double bond of the ketene and the C-N or C-C double bonds of the unsaturated imine. ELF topological analysis makes it possible to rule out an electrocyclic mechanism for the cyclisation step.

d-lactams vs b-lactams in Saudinger reactions

d-lactams vs b-lactams in Saudinger reactions

Article

Understanding the Polar Mechanism of the Ene Reaction.

A DFT Study.

Org. Biomol. Chem, 2014, 12, 7581-7590

The molecular mechanism of ene reactions has been characterised using DFT methods at the MPWB1K/6-311G(d,p) level of theory. Most reactions take place along a two-stage one-step mechanism in which the C-C bond formation takes place before the hydrogen transfer process. A very good correlation between the polar character of the reaction measured by the global electron density transfer at the transition state and the activation energy has been found. This behaviour allows establishing a useful classification of ene reactions in N-ene, having a very high activation energy, P-ene reactions having activation energies between 35 - 20 kcal/mol, and H-ene reactions having activation energies below 20 kcal/mol. ELF topological analysis permits the characterisation of the two-stage one-step mechanism associated with a two-centre nucleophilic /electrophilic interaction. Formation of the C-C single bond is achieved by the C-to-C coupling of two pseudodiradical centres formed at the two interacting carbon atoms in the first stage of the reaction. This topological analysis establishes that bonding changes are non-concerted. Finally, a DFT reactivity analysis makes it possible to characterise the electrophilic/nucleophilic behaviours of the reagents involved in ene reactions, and consequently, to predict the feasibility of ene reactions.

the Polar Mechanism of the Ene Reaction

the Polar Mechanism of the Ene Reaction

Article


Understanding the Mechanism of the Povarov Reaction. A DFT study.

RSC Adv., 2014,4, 25268

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The molecular mechanism of the Povarov reaction in acetonitrile has been studied at the MPWB1K/6-311G** level of theory. This reaction follows a domino process that comprises two sequential reactions: i) a Lewis acid catalysed aza-Diels-Alder (A-DA) reaction between a N-aryl imine and a nucleophilic ethylene yielding a formal [4+2] cycloadduct; ii) a stepwise 1,3-hydrogen shift at this intermediate affording the final tetrahydroquinoline. At this computational level, the Lewis acid catalysed A-DA reaction presents a two-step mechanism as a consequence of the large stabilisation of the corresponding zwitterionic intermediate. Our study allows establishing that the N-aryl substituent has no remarkable incidence in the activation energy, but the presence of a second C-aryl substituent has a relevant role in the reaction rate. Analysis of the DFT-based reactivity indices of the reagents provides further explanation of the behaviours of the mechanism of the A-DA reaction involved in the Povarov reaction.

Povarov Reaction

Povarov Reaction

Ionic Diels-Alder reactions

Ionic Diels-Alder reactions

Article

A DFT Analysis of the Participation of Zwitterionic TACs in

Polar[3+2]Cycloaddition Reactions.

Tetrahedron (2014) DOI: 10.1016/j.tet.2014.05.003

Unlike Diels-Alder reactions, which can be classified as non-polar Diels-Alder reactions with high activation energies, and polar Diels-Alder reactions with low activation energies [1],[3+2]cycloaddition (32CA) reactions lack a clear systematisation of their reactivity based on the nucleophilic/electrophilic behaviour of the reagents.

Based on the distortion/interaction energy model, Houk checked the 32CA reactions of nine different non-substituted tri-atom-components (TACs) with ethylene and acetylene, finding that the computed B3LYP/6-31G(d) activation enthalpies correlated very nicely with the distortion energies [2]. He concluded that the distortion energy of the TAC and ethylene or acetylene towards the TS is the major factor controlling the reactivity differences of TACs [2]. However, the distortion energy not has any chemical meaning because it depends on the TS geometry, thus does not providing any information about the structure/reactivity relationship of TACs

Very recently, we performed a structure/reactivity relationship study about the 32CA reactions of twelvenon-substitutedTACswith ethylene and acetylene, finding that the high reactivity of some TACs is due to itspseudodiradicalcharacter [3]. This study allowed establishing a useful classification of 32CA reactions intopseudodiradical-type (pr-type)reactions involving TACs with a highpseudodiradicalcharacter, which take place easily through an earlier TS with non-polar character, andzwitterionic-type(zw-type) reactions involving TACs with a high zwitterionic character, characterised by favourable nucleophilic/electrophilic interactions, taking place through polar TSs [3]. Considering that the simplest TACs of this series having a zwitterionic character presented low reactivity in non-polar processes towards ethyleneand acetylene, would be expected that the nucleophilic activation of these TACs and the electrophilic activation of ethylene, or vice versa, will favour the process towards a polar zw-typereaction.

In the present manuscript, a set of seven non-substituted TACs,showing a zwitterionic structureand low reactivity towards ethylene, has been studied using and nucleophilicity N reactivity indiceswthe electrophilicity defined within the conceptual DFT at the B3LYP/6-31G(d) level of theory. The general characteristic of these TACs is their high nucleophilic and a low electrophilic behaviour. Activation energies of the corresponding 32CA reaction computed at theMPWB1K/6-311G(d) level in dichloromethane point to that non-substituted TACsreact quickly toward dicyanoethylene showing their ability to react towards electron-deficient ethylenes. However, when the TACs are electrophilically activated by an appropriate substitution thereseems to be insufficient activation to react toward electron-rich ethylenes. The electrophilic activation of the TAC moiety for nucleophilic attacks was only determined by the coordination with a Lewis acid. All 32CA reactions studied in this work presented high regioselectivity. The polar character of these 32CA reactions is associated with the global charge transfer found at the TS, which is in agreement with azwitterionic-type(zw-type)mechanism. According to our results, the present theoretical study suggests that the substitution is required in both, TACs and the ethylene species, in order to experimentally perform these zw-type 32CA reactions under mild conditions.

1. Domingo, L. R.; Sáez, J. A.Org.Biomol. Chem.,2009,b7, 3576-3583.

2. Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187-10198.

3. Domingo, L. R.; Saez, J. A. J. Org.Chem. 2011,76, 373-379.

zw-type 32CA reactions

zw-type 32CA reactions

Article

The mechanism of ionic Diels-Alder reactions. A DFT study of the oxa-Povarov reaction.

RSC Adv. 2014, 4, 16567-16577

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The mechanism of the of ionic Diels-Alder (I-DA) reactions involved in oxa-Povarov reaction of a cationic aryl oxonium with cyclopentene and styrene has been studied using DFT methods at the B3LYP/6-31G* level.

While the I-DA reaction with cyclopentene takes place along atwo-stage one-stepmechanism, the presence of a phenyl substituent in styrene makes the mechanism of the I-DA reaction stepwise.

An electron localization function (ELF) bonding analysis of selected points along the IRCs of these I-DA reactions allows the establishment of a great similarity in bond formation along both one-step and two-step mechanisms.

The formation of the first C-C single bond begins in the short range of 1.95 - 1.90 Å, by the coupling of twopseudodiradicalcenters generated at the most electrophilic center of the cationic aryl oxonium and the most nucleophilic centers of cyclopentene and styrene, resulting in the global charge transfer that takes place along I-DA reactions. The use of the recently proposed radical Parr functions allows the characterization of the most electrophilic centers in cationic species and the most nucleophilic centers in anionic species.

Single-bond formation along the reaction coordinates

Single-bond formation along the reaction coordinates

An quantum chemical topological analysis of selected points along the IRCs of the one-step mechanism of the I-DA reaction between cationic aryl oxonium 6 and cyclopentene 7, in red, and the two-step mechanism of the I-DA reaction between 6 and styrene 12, in blue, allows the establishment of a great similarity in single bond formation along the two mechanisms. Both one-step and two-step mechanisms are non-concerted processes.

ELF similarity between P13 and IN1

ELF similarity between P13 and IN1

Reaction Forces

Complementarity of Reaction Force and Electron Localization

Function Analyses of Asynchronicity in Bond Formation

in Diels-Alder Reactions

D. Yepes, J. S. Murray, P. Pérez, L. R. Domingo, P. Politzer, P. Jaque

Physical Chemistry Chemical Physics

DOI: 10.1039/C3CP54766C (2014)


The reaction force constant, κ(ξ), together with the electron localization function (ELF) analyses of the bonding changes along the intrinsic reaction coordinate (IRC) associated with the polar Diels-Alder (P-DA) reaction between cyclopentadiene and the acroleine:BH3 complex have been studied. For this P-DA reaction, κ(ξ) presents a negative maximum with minima on both sides. The IRC point associated with this maximum shares the reaction path into the two-stages associated with the formation of each one of the two C-C single bonds. The topological ELF analysis of this point shows that while the first C-C single bond is practically formed, the formation of the second C-C has not started yet. Both, κ(ξ) and the ELF topological analyses of the structures involved in the reaction path corroborate that the formation of the two C-C single bonds is non-concerted.


Reaction Forces - ELF

Reaction Forces - ELF

A Review

State of the Art of the Bonding Changes along the Diels-Alder Reaction between Butadiene and Ethylene. Refuting the Pericyclic Mechanism

Abstract

Abstract

Bonding changes along the Diels-Alder reaction between butadiene 1 and ethylene 2 and related non-polar Diels-Alder reactions have been analysed using the bonding evolution theory (BET). Changes in electron density instead of molecular orbitals are used to rationalise the reaction mechanism. The electron localisation function (ELF) analysis indicates that C-C bond formation takes place by the C-to-C coupling of two pseudoradical centers formed along the reaction. The present review permits the establishment of two significant findings: i) the breaking of the C=C double bonds in butadiene 1 and ethylene 2 and the formation of the C-C single bonds in cycloadduct are non-concerted due to the changed in electron density required for the formation of the pseudoradical centers, and ii) the symmetric changes in electron density along these cycloadditions do not have a cyclic movement. These behaviours, which are opposite to the "concerted" and "close curve" bonding changes proposed for the pericyclic reactions allow to refute the pericyclic mechanism for Diels-Alder reactions.


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Understanding the Mechanisms of [3+2] Cycloaddition Reactions.

The Pseudodiradical versus the Zwitterionic Mechanism.


Tetrahedron 2014, 70, 1267-1273.


A New Classification of the [3+2] Cycloaddition Reactions

A New Classification of the [3+2] Cycloaddition Reactions

Analysis of the electronic structure of twelve three-atom-components (TACs), and their participation in [3+2] cycloaddition (32CA) reactions towards ethylene and acetylene allows establishing a useful classification of 32CA reactions into zw-type reactions involving TACs with a high zwitterionic character, and pr-type reactions involving TACs with a high pseudodiradical character. While propargylic-type TACs react towards a zw-type mechanism, some allylic-type TACs such as carbonyl and azomethine ylides, which present a high pseudodiradical character, appear to react quickly towards a pr-type mechanism.

This new classification improves the earlier classification made by R. Sustmann (Pure Appl. Chem., 1974, 40, 569) in normal- and inverse-electron demand reactions, since this does not report any information about the polar or non-polar nature of the reactions, nor about the feasibility of the reaction.

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A base catalysis in the C-C bond-formation on the NHC catalysed addition of enols to acyl-azoliums.

A base catalysis in the C-C bond-formation on the NHC catalysed addition of enols to acyl-azoliums.
Org. Biomol. Chem., 2014, 12, 895-904.

A DFT study (MPWB1K/6-31G**) of the NHC catalysed Michael addition of enols to a,b-unsaturated acyl-azoliums shows that along the direct and the conjugated additions, formation of a hydrogen bond of enols with the carboxyl oxygen is not sufficient to favour the C-C bond formation as a consequence of the low nucleophilic character of enols. Interestingly, when enols form a hydrogen bond with the chloride counterion, the activation energies associated with the conjugated addition decrease as a consequence of the increased nucleophilic character of enols and the increased electrophilic character of the 'acyl-azolium + Cl' ion pair. Analysis of the DFT reactivity indices allows establishing a base catalysis for the C-C bond-formation step promoted by the chloride counterion [213].

The Mechanism of the Diels-Alder Reaction.

The Mechanism of the Diels-Alder Reaction

R. B. Woodward

J. Am. Chem. Soc. 1942, 64, 3058-3059

In 1942 R. B. Woodward published a communication to the editor of the J. Am. Chem. Soc. titled "The Mechanism of the Diels-Alder reaction" (J. Am. Chem. Soc. 1942, 64, 3058), in which he proposed an ionic mechanism based on the electron transfer from a substance, e. g., a diene, of relatively low ionization potential and, on the other, a molecule of high electron affinity, e. g., a a,b-unsaturated carbonyl compound. This communication can be considered the earliest theoretical proposal of our polar Diels-Alder mechanism (Org. Biomol. Chem. 2009, 7, 3576).

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Communication

Parr Functions

Building upon our recent studies devoted to the bonding changes in polar reactions [186, 188], we have proposed two new electrophilic,P+, and nucleophilic, P-, Parr functions based on the spin density distribution at the radical anion and at the radical cation of a neutral molecule [202].

These local functions allow for the characterisation of the most electrophilic and nucleophilic centres of molecules, and for the establishment of the regio- and chemoselectivity in polar reactions.

The proposed Parr functions are compared both ,with the Parr-Yang Fukui functions [J. Am. Chem. Soc. 1984, 106, 4049] based on the frontier molecular orbitals, and Yang-Mortier condensed Fukui functions [J. Am. Chem. Soc. 1986, 108, 5708] based on Mulliken charges [202].


Parr functions derived from the atomic spin density of the cation, anion and neutral radicals.

Parr function in intramolecular processes

Parr function in intramolecular processes
Electrophilic and nucleophilic Parr functions in an intramolecular Diels-Alder reaction.

C-C bond formation in polar processes

C-C bond formation in polar processes
C3-C4 bond formation by C-to-C coupling of two pseudoradical centers located on the C3 an C4 atoms.

The topologic ELF analysis of the C-C bond formation in the Friedel-Crafts reaction between indoles and nitroolefins indicates that it takes place by a C-to-C coupling of two pseudoradical centers located at the most electrophilic center of nitroethylene and the most nucleophilic center of N-methyl indole [203]. These relevant centers are achieved via the global charge transfer process that takes place from nucleophilic indole to electrophilic nitroethylene [202].

This reactivity model, which is shown in polar Diels-Alder and 1,3-dipolar cycloaddition reactions [186, 200 and 201] , is opposite to that in which indole attacks nucleophilically to the conjugated position of nitroethylene.


Electron density maps along the C-C bond formation

At 2.00 Å it can be observed the gathering of electron density on the most nucleophilic center of indole and on the most electrophilic center of nitroethylene.

Note that the electron density accumulation at the most electrophilic center of nitroethylene, which is in agreement with my definition of electrophilic center [186 and 202], is contrary to the accepted definition of center with electron deficiency.

POLAR VERSUS NON-POLAR DIELS-ALDER REACTIONS

POLAR VERSUS NON-POLAR DIELS-ALDER REACTIONS

The charge transfer (CT) found at the TSs of Diels-Alder reactions controls the activation energies of this type of cycloaddition reactions [151]. This behaviour has allowed to classify Diels-Alder reactions as non-polar (N-DA) and polar (P-DA).

The polar character of Diels-Alder reactions, and thus their experimental feasibility, can be anticipated analysing the electrophilic and nucleophiles behaviours of the diene and the ethylene.

These proprieties of the organic molecules can be easily obtained by means of the electrophilicity and nucleophilicity indices defined within the conceptual Density Functional Theory (DFT).

logarithm of the experimental rate constant versus calculated CT at the TS

logarithm of the experimental rate constant versus calculated CT at the TS
A good correlation is found for the P-DA reactions between Cp and the tetracyanoethylene series.

the polarity increases with the electrophilic character of the ethylene

the polarity increases with the electrophilic character of the ethylene

New Concept of electrophilic centers

New Concept of electrophilic centers
Electrophilic centres have been related with positively charged centres. Thus, in carbonyl compounds, the carbon atom is associated with the most electrophilic atom.

Our recent studies have established that the most electrophilic centres are those receiving most of the electron density along the global charge transfer from the nucleophile to the electrophile.
Thus, in benzoquinones, the most electrophilic centres are oxygen atoms, in spite of being negatively charged [186].

Analysis of the recently proposed Parr functions allows for the characterization of the most electrophilic and nucleophilic centres of a molecule [202].

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