Unravelling [3+2] cycloaddition reactions through the molecular electron density theory

Abstract

After the first classification of [3+2] cycloaddition (32CA) reactions into zw-type and pr-type reactions, established in 2014, the structure and reactivity of the most important three-atom-components (TACs) used in 32CA reactions has been completely characterised within the recently proposed Molecular Electron Density Theory (MEDT). Among the huge amount of work developed along the present Ph.D thesis, eight representative publications have been selected and discussed herein, which allowed characterising two new reactivity types as well as consolidating the original zw-type reactivity. Thus, depending on the four different electronic structures of TACs, i.e. pseudodiradical, pseudoradical, carbenoid and zwitterionic, 32CA reactions have been classified into pdr-, pmr-, cb- and zw-type reactions. While pdr-type 32CA reactions are the fastest, zw-type reactions are the slowest. The different electronic structures at the ground state of the reagents account for this reactivity trend and reveal that the reactivity of carbenoid TACs is different. In addition, no TAC can be considered a 1,2-zwitterionic structure as proposed for “1,3-dipoles”. The polar character of the reaction, measured by the global electron density transfer value computed at the transition state structure (TS), affects the four reactivity types in such a manner that the stronger the nucleophilic/electrophilic interactions taking place at the TS, the faster the reaction, and may even change the molecular mechanism according to the Parr functions defined within Conceptual DFT. This MEDT rationalisation of 32CA reactions unravels classical Huisgen’s and Firestone’s mechanistic proposals established in the 60’s. Regardless of the reactivity type and polar character of the reaction, topological analysis of the electron localisation function along one-step 32CA reactions suggests that the bonding changes are not “concerted”, but sequential, thus ruling out the classification of these reactions as “pericyclic”. In the present thesis, the classical theory of 32CA reactions, established in the 60’s of the past century and still prevailing today, is revisited and reinterpreted based on MEDT. A solid new reactivity model for 32CA reactions is established, emphasising that the way that organic chemists conceive organic chemistry demands a contemporary revision aimed towards the analysis of electron density.