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The regioselective hetero-Diels-Alder (HDA) reaction of asymmetric tetrazines (TTZs) with electron-rich (ER) ethylenes has been studied with use of DFT methods at the B3LYP/6-31G* level of theory. The reaction is a domino process that comprises three consecutive reactions: (i) a HDA reaction between the TTZ and the ER ethylene; (ii) a retro-Diels-Alder reaction with loss of nitrogen; and (iii) a beta-hydrogen elimination with formation of the final pyridazines. The first polar HDA reaction, which is associated to the nucleophilic attack of the ER ethylene to the electrophilically activated TTZ, is the rate and regioselectivity determining step of the domino process. The unexpected regioselectivity of these HDA reactions is explained within the polar cycloaddition model by using the conceptual DFT. Although the nucleophilic attack of the ER ethylene over the para position relative to the methylsulfinyl substituent could favor the charge transfer, it is energetically more unfavorable because it diminishes the electron density at the electronegative TTZ core.

The molecular mechanism for the reaction between 1-methylpyrrole and dimethyl acetylenedicarboxylate (DMAD) has been studied using ab initio methods. Two alternative reaction pathways have been considered, both of which correspond to stepwise processes with initial, rate-determining formation of a common zwitterionic intermediate. This intermediate is formed by nucleophilic attack of the pyrrole ring to the carbon−carbon triple bond of DMAD. Closure of this intermediate (pathway A) affords a [4 + 2] cycloadduct, whereas intramolecular proton transfer (pathway B) affords a Michael adduct. The much larger potential energy barrier of the second step in pathway B relative to pathway A is responsible for the nonoccurrence of the former. Inclusion of solvent effects, by means of a polarizable continuum model, does not modify the electronic nature of this molecular mechanism.

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The reactions of electrophilically activated benzonitrile N-oxides (BNOs) toward 3-methylenephthalimidines (MPIs) have been studied using density functional theory (DFT) at the B3LYP/6-31G* level. For these reactions, two different channels allowing the formation of the [3 + 2] cycloadducts and two isomeric (E)- and (Z)-oximes have been characterized. The 1,3-dipolar cycloadditions take place along concerted but highly asynchronous transition states, while formation of the oximes is achieved through a stepwise mechanism involving zwitterionic intermediates. Both reactions are initiated by the nucleophilic attack of the methylene carbon of the MPIs to the carbon atom of the electrophilically activated BNOs. The analysis based on the natural bond orbital (NBO) and the topological analysis of the electron localization function (ELF) at the transition structures and intermediates explains correctly the polar nature of these reactions. Solvent effects considered by the PCM model allow explaining the low incidence of the solvent polarity on the rate and composition of the reactions.