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PW-3. Benchmarking the B3LYP, MPWB1K and M06-2X DFT functionals in the study of cycloaddition reactions.
PW-1. Poster presented in the VI Mediterranean Organic Chemistry Meeting. Granada (Spain) 2013
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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.
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.
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.
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.
A Bonding Evolution Theory Study of the Mechanism of
Mar Ríos-Gutiérrez, Patricia Pérez and Luis R. Domingo
RSC Adv. 2015, 15, 58464-58477
The mechanism of zw-type
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
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.
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.
A DFT Study of the Ionic
Luis R. Domingo, Mar Ríos-Gutiérrez and Patricia Pérez
Tetrahedron 2015, 71, 2421-2427,
The molecular mechanism of the ionic
A Mechanistic Study of the Participation of Azomethine Ylides and Carbonyl Ylides in
Tetrahedron 2015, 71, 1050-1057.
The participation of azomethine ylides (AYs) and carbonyl ylides (CYs) in
Why Houk's distortion/interaction energy model is an erroneous reactivity model.
WHY DIELS-ALDER REACTIONS ARE NON-CONCERTED PROCESSES
J. Chil. Chem. Soc., 2014, 59, 2615.2618
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.
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
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.
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.
Understanding the Mechanism of the Povarov Reaction. A DFT study.
RSC Adv., 2014,4, 25268
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
A DFT Analysis of the Participation of Zwitterionic TACs in
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 ,
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 . 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 . 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 . 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 . 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.
The mechanism of ionic Diels-Alder reactions. A DFT study of the oxa-Povarov reaction.
RSC Adv. 2014, 4, 16567-16577
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.
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
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.
State of the Art of the Bonding Changes along the Diels-Alder Reaction between Butadiene and Ethylene. Refuting the Pericyclic Mechanism
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.
Understanding the Mechanisms of
The Pseudodiradical versus the Zwitterionic Mechanism.
Tetrahedron 2014, 70, 1267-1273.
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.
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 .
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).
Building upon our recent studies devoted to the bonding changes in polar reactions
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
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
This reactivity model, which is shown in polar Diels-Alder and 1,3-dipolar cycloaddition reactions
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
The charge transfer (CT) found at the TSs of Diels-Alder reactions controls the activation energies of this type of cycloaddition reactions
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).
Analysis of the recently proposed Parr functions allows for the characterization of the most electrophilic and nucleophilic centres of a molecule .