Internal Hydrogen Bond Influences the Formation of [2+2] Schiff Base Macrocycle: Open-Chain Vs. Hemiaminal and Macrocycle Forms

Open-chain vs. hemiaminal and macrocycle forms of the condensation product of 2,6-diformylpyridine and opposite enantiomers of trans-1,2-diaminocyclopentane have been studied using DFT methods to reveal that the macrocycle (with a water molecule co-product) is the thermochemically preferred form. The mechanistic picture of formation of [[2+2]] Schiff base macrocycle from its chain precursor has been supplemented with the electron localization function analysis revealing the crucial electronic aspects underlying the covalent bonds evolution. The macrocycle formation may proceed along two paths, through two distinct diastereoisomerc hemiaminal intermediates. The reaction rate limiting water elimination step exhibits the considerably lower and unusually flat energy barrier for the path involving S hemiaminal due to the strong decoupling of the CO bond cleavage from the proton migration to form the water molecule.