A molecular electron density theory study of the participation of tetrazines in aza-Diels–Alder reactions

Abstract

The reactions of eight tetrazines of increased electrophilic character with nucleophilic tetramethyl ethylene (TME) and with electrophilic tetracyanoethylene (TCE) have been studied using 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 an increase of the electrophilicity and a decrease of the nucleophilicity of tetrazines with an 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 with the continuous depopulation of the C-C and C-N double bonds. † Electronic supplementary information (ESI) available: Figure with the geometries of MCa and MCh. Figures with the attractor positions of the ELF valence basins of the relevant IRC structures of the ADA reaction between dinitro tetrazine 14a and TME 15, and those of TS1a-h.Table with MPWB1K/6-311G(d,p) global CDFT reactivity indices for the studied reagents. Tables with the MPWB1K/6-311G(d,p) electronic energies, enthalpies, entropies and Gibbs free energies for the stationary points involved in the domino reactions of the series tetrazine derivatives 14a-h with TME 15, and those of the domino reactions of the series tetrazine derivatives 14f-h with TCE 18. Table with the MPWB1K/6-311G(d,p) unique imaginary frequency of TS1a-k and TS2a-k. See

Unveiling the Reactivity of Cyclic Azomethine Ylides in [3+2] Cycloaddition Reactions within the Molecular Electron Density Theory

“…Thus, this 32CA reaction is classified as FEDF reaction. [18] Note that this classification of the organic reactions based on the flux of the GEDT is more accurate than that based on the Sustmann's MO based classification, [22] since Sauer categorised the non-polar 32CA reaction with cyclooctyne 17 as "LUMO dipole -HOMO dipolarophile -controlled". [10] This comparative study indicates that the high reactivity shown by experimental cyclooctyne 17 is a consequence of the strain present in this cycloalkyne, which experience a non-polar reactivity.…”

“…The analysis of the natural charges [21] shows that AYs 13a and 18 present an identical electronic distribution at the core framework. While the C1 and N2 centres are negatively charged by ca -0.19 (13a) and -0.21 (18), and -0.26 (13a) and -0.28 (18) e, respectively, the C3 carbon is positively charged by 0.25 e in both AYs. This charge distribution is a consequence of the presence of the two EW -CN groups at the C1 carbon, which strongly polarize the electron density towards the C1 carbon.…”

“…Analysis of the nucleophilic P k -Parr functions of cyclic AYs 13a and 18 indicates that the substituted C1 carbon is the most nucleophilic centre of these species presenting the maximum value, P k -= 0.57 (13a) and 0.54 (18) eV. On the other hand, the analysis of the electrophilic P k + Parr functions of cyclic AYs 13a and 18 indicates that both the C1 and C3 carbons have a similar low electrophilic activation (see Figure 2).…”

“…While the reactions involving electrophilic acetylenes are classified as FEDF reactions, since the electron density fluxes from the AY framework towards the ethylene one, that involv-ing nucleophilic DMAP 15 is classified as an REDF reaction, since the electron density fluxes from the ethylene framework towards the AY one, in agreement with the CDFT analysis. [18] On the other hand, the non-polar 32CA reaction with acetylene 22 should be classified as the null electron density flux (NEDF).…”

Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory

“…Reactions with GEDT values below 0.05 e correspond to non-polar processes, while values above 0.20 e correspond to polar processes. Very recently, organic reactions have been classified as forward electron density flux (FEDF) and reverse electron density flux (REDF) reactions, depending on the direction of the flux of the electron density at the TS [28]. Non-polar reactions are classified as null electron density flux (NEDF) reactions [29].…”