Diels–Alder Reactivities of Benzene, Pyridine, and Di-, Tri-, and Tetrazines: The Roles of Geometrical Distortions and Orbital Interactions

Abstract

The cycloadditions of benzene and ten different azabenzenes (pyridine, three diazines, three triazines, and three tetrazines) with the ethylene dienophile have been explored with density functional theory (M06-2X) and analyzed with the distortion/interaction model. Activation barriers correlate closely with both distortion energies and interaction energies over an activation energy range of 45 kcal/mol. The replacement of CH with N increases Diels-Alder reactivity due not only to the more favorable orbital interaction, but also to a decrease in distortion energy. The rates of reactions are greatly influenced by the nature of the bonds being formed: two C-C bonds > one C-C bond, and one C-N bond > two C-N bonds. The activation energy of Diels-Alder reactions correlates very well with reaction energies and with the NICS(0) values of the aromatic dienes. The distortion energy of the Diels-Alder reaction transition states mostly arises from the diene out-of-plane distortion energy.

Tetrazine ligation for chemical proteomics

“…2a) [21, 22]. Among three different possible tetrazine isomers, 1,2,4,5-tetrazine is used for the iEDDA reaction [23].…”

Confinement induced thermodynamic and kinetic facilitation of some Diels–Alder reactions inside a CB[7] cavitand

“…The computed diameters of the host along both the directions as a result of guest encapsulation have been presented in Supporting Information Table S1. It is worth noting that we have only considered the concerted and synchronous pathway for the reactions under consideration. At the reactant complex for the reaction 1, the two reacting moieties, viz., benzene and ethylene remain in a slightly tilted orientation with respect to one another.…”

“…Benzene, an archetype of aromatic molecules, is rarely employed in a Diels–Alder reaction as a diene. The reason for this could be gauged from the fact that by taking part in a Diels–Alder reaction the inherent aromatic stabilization of benzene gets lost and as a result such a reaction would require high activation barrier . Different methods have been explored by experimentalists to increase the propensity of benzene to take part in a Diels–Alder reaction.…”

Does Confinement Always Lead to Thermodynamically and/or Kinetically Favorable Reactions? A Case Study using Diels–Alder Reactions within ExBox+4and CB[7]

“…Clearly,t he preorganization of the reactants inside CB [7] as ar esult of confinementf acilitates the step leadingt o the formation of TS, because the reactants have to undergo smaller geometricala djustments to reach the TS stage. At this point it is worth noting that Houk and co-workers [54] have shown ar elationship between the activation energy barrier and the distortion incurred on the reacting fragments in the case of Diels-Alder reaction. Their investigation indicates that if the reactants requires ignificant distortion to participate in the reaction, the corresponding activation barrier would undergo an increment as compared with cases in whichl ess structural distortion is needed.…”