Diels–Alder Reactivities of Strained and Unstrained Cycloalkenes with Normal and Inverse-Electron-Demand Dienes: Activation Barriers and Distortion/Interaction Analysis

Abstract

The Diels-Alder reactions of the cycloalkenes, cyclohexene through cyclopropene, with a series of dienes--1,3-dimethoxybutadiene, cyclopentadiene, 3,6-dimethyltetrazine, and 3,6-bis(trifluoromethyl)tetrazine--were studied with quantum mechanical calculations and compared with experimental values when available. The reactivities of cycloalkenes as dienophiles were found by a distortion/interaction analysis to be distortion controlled. The energies required for cycloalkenes to be distorted into the Diels-Alder transition states increase as the ring size of cycloalkenes increases from cyclopropene to cyclohexene, resulting in an increase in activation barriers. The reactivities of the dienes are controlled by both distortion and interaction energies. In normal Diels-Alder reactions with cycloalkenes, the electron-rich 1,3-dimethoxybutadiene exhibits stronger interaction energies than cyclopentadiene, but the high distortion energies required for 1,3-dimethoxybutadiene to achieve transition-state geometries overtake the favorable interaction, resulting in higher activation barriers. In inverse-electron-demand Diels-Alder reactions of 3,6-dimethyltetrazine and 3,6-bis(trifluoromethyl)tetrazine, the reactivities are mainly controlled by interaction energies.

Deeper Insight into the Diels–Alder Reaction through the Activation Strain Model

“…The computed different distortion energies directly correlate with the out-of-plane dihedral angles of the cycloalkenes, which, in turn, are related to the scharacter of the respective olefinic carbon atoms. [29] Similar conclusions, that is, the strain energy as the major factor controlling the reactivity, have been drawn by Houk and co-workers when exploring the DA reactivities of cycloalkenones and cyclic dienes [30] and more recently, when investigating the effect of substituents at the 5-position of hyperaromatic cyclopentadienes [31] in their DA reactions with ethylene. [32] 3.3.…”

Fluorogenic protein labeling using a genetically encoded unstrained alkene

“…34 HOMO (alkene) of higher energy level benefits an iEDDA reaction between an alkene and a tetrazine. 35,36 Although the styrene–tetrazine reaction is slower than certain reactions between strained alkenes and tetrazine (entry 7, 8, 10, Table S1†), 10,11,15–27 its rate is comparable to the strain-promoted cycloaddition of fluorinated cyclooctynes with azides 37 (entry 11, Table S1†) and the first generation of cyclopropene–tetrazine reaction (entry 9, Table S1†), 26 which have been successfully applied to the labeling of biomolecules in live cells. 26,30,31,33,37 …”

Photo-Triggered Click Chemistry for Biological Applications

“…It is characterized by high yield under various conditions, insensitive toward solvent polarity, and little byproducts. Indeed, the tetrazine/ trans -cyclooctene based inverse electron-demand DA reaction has become the most popular bioorthogonal reaction in the literature because of its fast reaction kinetics [76]—second-order rate constant as high as 2.8 × 10 6 M −1 s −1 has been reported [77]. So far, two photo-triggered hetero-dienes have been exploited in the DA reactions for biological use, namely, o -quinone methides and hydroxy- o -quinodimethanes.…”