Unveiling the High Reactivity of Benzyne in the Formal [3+2] Cycloaddition Reactions towards Thioamides through the Molecular Electron Density Theory
Lydia Rhyman, Mar Ríos-Gutiérrez, Luis R. Domingo, Ponnadurai Ramasami
The domino reaction of benzyne with thioamide has been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d) level. This domino reaction takes place through i) a formal [3+2] cycloaddition (32CA) reaction affording an ammonium ylide, and ii) an extrusion of ethylene from this species yielding a dihydrothyazole. Topological analysis of the electron density of benzyne shows its pseudodiradical structure, that is, without any energy cost, changes to a carbenoid one, allowing its participation as electrophile in polar reactions. As a consequence, the formal 32CA reaction does not has activation enthalpy. Analysis of the changes of electron density along the domino reaction indicates that while the formal 32CA reaction takes place through a two-stage one-step mechanism, the extrusion of ethylene takes place through an intramolecular E2 elimination mechanism. The present MEDT study reveals the chameleonic structure/reactivity of benzyne, allowing its participation in both non-polar and polar reaction with an unappreciable activation enthalpy.
Unravelling the Strain-Promoted [3+2] Cycloaddition Reactions of Phenyl Azide with Cycloalkynes from the Molecular Electron Density Theory Perspective
Luis R Domingo, Nivedita Acharjee
New J. Chem. (2020)
The strain-promoted [3+2] cycloaddition (SP-32CA) reactions of phenyl azide with a series of five strained cycloalkynes C5–C9 have been studied within molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. These zwitterionic type SP-32CA reactions take place through a one-step mechanism, with activation enthalpies in acetonitrile between 4.2 and 19.9 kcal·mol-1. An excellent linear correlation between the decrease in activation enthalpies and the ring size of this series of cycloalkynes can be established. The present study shows that the highly strained cycloalkynes C5 and C6 experience a different chemical reactivity than less strained cycloalkynes C7 – C9, caused by the noticeable electrophilic character of the former ones. The present MEDT study permits establishing that the loss of the cycloalkyne strain along the reaction path together with easy depopulation of the CCºCC bonding region along these SP-32CA reactions, and not “less distortion of the 1,3-dipole in the transition state geometry“, as has been suggested, is responsible for the kinetics and thermodynamics of these SP-32CA reactions.
Unveiling the Lewis Acid Catalysed Diels–Alder
the Molecular Electron Density Theory.
Luis R. Domingo, Mar Ríos-Gutiérrez, Patricia Pérez.
Molecules 2020, 25, 2535.
The effects of metal-based Lewis acid (LA) catalysts on the reaction rate and regioselectivity in polar Diels-Alder (P-DA) reactions has been analysed within the molecular electron density theory (MEDT). A clear correlation between the reduction of the activation energies and the increase of the polar character of the reactions measured by analysis of the global electron density transfer at the corresponding transition state structures (TS) is found, a behavior easily predictable by analysis of the electrophilicity w and nucleophilicity N indices of the reagents. The presence of a strong electron-releasing group in the diene changes the mechanism of these P-DA reactions from a two-stage one-step to a two-step one via formation of a zwitterionic intermediate. However, this change in the reaction mechanism does not have any chemical relevance. This MEDT study makes it possible to establish that the more favourable nucleophilic/electrophilic interactions taking place at the TSs of LA catalysed P-DA reactions are responsible for the high acceleration and complete regioselectivity experimentally observed.
A Molecular Electron Density Theory Study of the Reactivity of
Tetrazines in Aza-Diels-Alder Reactions.
Luis R. Domingo, Mar Ríos-Gutiérrez, Patricia Pérez.
RSC Adv. 2020, 10, 15394–15405.
The reactions of eight tetrazines of increased electrophilic character with nucleophilic tetramethyl ethylene (TME) and with electrophilic tetracyanoethylene (TCE) have been studied within the Molecular Electron Density Theory. These reactions are domino processes comprising an aza-Diels-Alder (ADA) reaction followed by an extrusion of molecular nitrogen, yielding a dihydropyridazine. Analysis of the conceptual DFT (CDFT) indices showed the increase of the electrophilicity and the decrease of the nucleophilicity of tetrazines with the increase of the electron-withdrawing character of the substituent. A very good correlation between the global electron density transfer at the transition structures and the activation enthalpies for the ADA reactions involving TME was found. However, tetrazines have no tendency to react with electrophilic ethylenes such as TCE. Bonding Evolution Theory (BET) analysis of the ADA reaction of dinitro tetrazine with TME showed that the activation energy is mainly associated to the continuous depopulation of the C-C and C-N double bonds.
Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine
and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with
(R)-Carvone through the Molecular Electron Density Theory.
M. Ríos-Gutierrez, L. R. Domingo, M. Esseffar, A. Oubella, M. Y. Ait Itto
Molecules 2020, 25, 1085
The [3+2] cycloaddition (32CA) reactions of diphenyl nitrilimine and phenyl nitrile oxide with (R)-carvone have been studied within the Molecular Electron Density Theory (MEDT). Electron localisation function (ELF) analysis of these three-atom-components (TACs) permits its characterisation as carbenoid and zwitterionic TACs, thus having different reactivity. Analysis of the conceptual DFT indices accounts for the very low polar character of these 32CA reactions, while analysis of the DFT energies accounts for the opposite chemoselectivity experimentally observed. Topological analysis of the ELF along the single bond formation makes it possible to characterise the mechanisms of these 32CA reactions as cb- and zw-type. The present MEDT study supports the proposed classification of 32CA reactions into pdr-, pmr-, cb- and zw-type, thus asserting the MEDT as the theory able to explain chemical reactivity in Organic Chemistry.
A Molecular Electron Density Theory Study of the Enhanced Reactivity of
Aza Aromatic Compounds Participating in Diels-Alder Reactions.
Luis R. Domingo, Mar Ríos-Gutiérrez, Patricia Pérez
Org. Biomol. Chem. 2020,18, 292 –304
The enhanced reactivity of a series of four aza aromatic compounds (AACs) participating in the Diels-Alder (DA) reactions with ethylene has been studied within the Molecular Electron Density Theory (MEDT). The analysis of the electronic structure of these AACs allows establishing that the substitution of the CH unity by the isoelectronic N: unity linearly decreases the ring electron density (RED) of these compounds and concomitantly decreases their aromatic character and increases their electrophilic character. These behaviours do not only decrease drastically the activation energies of these DA reactions, but also increase the reaction energies when they are compared with the very unfavourable DA reaction between benzene and ethylene. Very good correlations between the NICS(0) values and the electrophilicity indices of these AACs with the RED values are found. The present MEDT study makes it possible to establish two empirical electron density unity (EDU) indices accounting for the contribution of the ñC and the ñN unities, 2.77 and 2.19 e, respectively, for the RED, which is mainly responsible for the reactivity of these AACs. Comprehensive chemical concepts such as electron density, aromaticity and electrophilicity make it possible to explain the chemical reactivity of these AACs participating in DA reactions towards ethylene.
Are One-Step Aromatic Nucleophilic Substitutions of Non-Activated
Benzenes Concerted Processes?.
Luis R. Domingo, Mar Ríos-Gutiérrez, Eduardo Chamorro and Patricia Pérez.
Org. Biomol. Chem. 2019, 17, 8185 – 8193
The aromatic nucleophilic substitution (SNAr) reactions of non-electrophilically activated benzenes have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311+G(d) computational level. These reactions, taking place through a one-step mechanism, present a high activation Gibbs free energy, DG≠ = 31.0 kcal·mol-1, which decreases to 22.1 kcal·mol-1 in the intramolecular process. A topological analysis of the electron localisation function along the reaction paths permits establishing the non-concerted nature of these SNAr reactions. A series of unstable structures, with similar electronic structures than those of Meisenheimer intermediates, are characterised. The present MEDT study makes it possible to establish that even these one-step SNAr reactions involving only two single bonds are non-concerted processes.
On the Nature of Organic Electron Density Transfer Complexes
within the Molecular Electron Density Theory
L. R. Domingo; M. Ríos-Gutiérrez
Org. Biomol. Chem. 2019, 17, 6478–6488
The structural features of a series of organic molecular complexes formed between the strong electrophilic tetracyanoethylene and twelve benzene derivatives of increased nucleophilic character, herein named Electron Density Transfer Complexes (EDTCs), have been studied within the Molecular Electron Density Theory. The favourable nucleophilic/electrophilic interactions, which favour the global electron density transfer (GEDT) towards the electrophile, are responsible for the formation of these species. Molecular complexes presenting a GEDT above 0.05 e are classified as EDTCs. Analysis of the Parr functions at the separated reagents as well as the topological analysis of the electron density at the EDTCs allow understanding the subtle changes in the electronic structure of this significant class of molecular complexes, and consequently, their physical properties.
An MEDT Study of the Mechanism and Selectivities of the [3+2]
Cycloaddition Reaction of Tomentosin with Benzonitrile Oxide.
Abdellah Zeroual, Mar Ríos-Gutiérrez, Mohammed El Idrissi,
Habib El Alaoui El Abdallaoui, Luis R. Domingo
Int. J. Quantum Chem. 2019, e25980
The [3+2] cycloaddition (32CA) reaction of tomentosin with benzonitrile oxide yielding a spiro-isoxazoline has been studied within the Molecular Electron Density Theory at the B3LYP/6-31(d,p) computational level. Given the multifunctionality of tomentosin, this 32CA reaction can take place along sixteen competitive reaction paths. The chemo-, regio- and stereoisomeric reaction paths involving the two C-C double bonds of tomentosin have been studied. DFT calculations account for the total chemo- and regioselectivity, in complete agreement with the experimental outcomes, being suggestive of low diastereofacial selectivity. Analysis of the Conceptual DFT indices accounts for the non-polar character of this 32CA reaction. On the other hand, the topological analysis of the ELF of the selected points of the IRC associated with the formation of the C-C and C-O single bonds emphasizes the zw-type reactivity of the phenyl nitrile oxide; the reaction taking place through a non-concerted two-stage one-step mechanism initialized with the formation of the C-C single bond involving the -conjugated carbon of tomentosin.
A Molecular Electron Density Theory Study of the Chemoselectivity,
Regioselectivity and Diastereofacial Selectivity in the Synthesis of
an Anti-Cancer Spiro-Isoxazoline derived from α-Santonin.
L. R. Domingo, M. Ríos-Gutiérrez and N. Acharje
Molecules 2019, 24, 832
The [3+2] cycloaddition (32CA) reaction of an α-santonin derivative having an exocyclic C-C double bond with p-bromophenyl nitrile oxide yielding only one spiro-isoxazoline has been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. Analysis of the conceptual DFT reactivity indices and the global electron density transfer account for the non-polar character of this zwitterionic-type 32CA reaction, which presents an activation enthalpy of 13.3 kcal·mol−1. This 32CA reaction takes place with total ortho regio- and syn diastereofacial selectivity involving the exocyclic C-C double bond, in complete agreement with the experimental outcomes. While both, the more favourable C-C bond formation involving the -conjugated carbon of α-santonin derivative than the C-O one is responsible for the ortho regioselectivity, the favourable electronic interactions taking place between the oxygen of the nitrile oxide and two axial hydrogen atoms of the α-santonin derivative are responsible for the syn diastereofacial selectivity.
The Carbenoid-Type Reactivity of Simplest Nitrile Imine from
a Molecular Electron Density Theory perspective.
M. Ríos-Gutiérrez and L. R. Domingo
Tetrahedron 2019, 75, 1961-1967
The [3+2] cycloaddition (32CA) reactions of the simplest nitrile imine (NI) with ethylene and electrophilic dicyanoethylene (DCE) have been studied within the Molecular Electron Density Theory (MEDT) with the aim of characterising its reactivity. Topological analysis of the electron localisation function (ELF) of NI shows that it has a carbenoid structure. The activation energy of the 32CA reaction of the simplest nitrile imine with dicyanoethylene is 5.6 kcal·mol-1 lower than that involving ethylene, in agreement with the high polar character of the former reaction. Bonding Evolution Theory accounts for the cb-type reactivity of nitrile imine. Along the more favourable ortho regioisomeric path associated with the 32CA reaction involving dicyanoethylene, which takes place through a non-concerted two-stage one-step mechanism, formation of the first C3-C4 single bond takes place at a C-C distance of 2.02 Å, by donating the non-bonding electron density of the carbenoid center of nitrile imine to the -conjugated C4 carbon of dicyanoethylene.
Unveiling the high reactivity of cyclohexynes in [3 + 2] cycloaddition
reactions through the molecular electron density theory.
L. R. Domingo, Mar Ríos-Gutiérrez and Patricia Pérez
Org. Biomol. Chem. 2019, 17, 498–508
The [3+2] cycloaddition (32CA) reactions of cyclohexyne, a cyclic strained acetylene, with methyl azide and methoxycarbonyl diazomethane have been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d) computational level. These 32CA reactions, which take place through a one-step mechanism involving highly asynchronous transition state structures, proceed with relatively low activation enthalpies of 6.0 and 4.3 kcal·mol-1, respectively, both reactions being strongly exothermic. The reactions are initiated by the creation of a pseudoradical center at one of the two acetylenic carbons of cyclohexyne with a very low energy cost, 1.0 kcal·mol-1, which promotes the easy formation of the first C-N(C) single bond in the adjacent acetylenic carbon. This scenario is completely different from that of the 32CA reaction involving non-strained but-2-yne; thus, strain in cyclohexyne triggers a high reactivity as a consequence of its unusual electronic structure at the ground state. Finally, the experimental regioselectivity of the 32CA reactions involving 3-alkoxy-cyclohexyne derivatives is correctly explained within MEDT.
High reactivity of cyclohexyne
Unveiling the High Reactivity of Cyclohexynes in [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory
Coordination of BF3 LA to the oxygen of formaldehyde drastically accelerates both reactions given the high electrophilic character of the BF3:formaldehyde complex. As a consequence, these reactions present a very low activation enthalpy, less than 2.2 kcal·mol-1, thus becoming competitive. In dioxane, the P-AE reaction is slightly favoured because of the larger polar character of the corresponding transition state (TS) structure.
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
How does the Global Electron Density Transfer Diminish Activation Energies in Polar Cycloaddition Reactions? A Molecular Electron Density Theory Study
ChemistrySelect 2016, 1, 6026 - 6039.
Electrophilic activation of CO2 in cycloaddition reactions towards a nucleophilic carbenoid intermediate: new defying insights from the Molecular Electron Density Theory.