Intramolecular Natural Energy Decomposition Analysis: Applications to the Rational Design of Foldamers.

We describe an intramolecular version of the natural energy decomposition analysis (NEDA), with the aim of evaluating interactions between molecular fragments across covalent bonds. The electronic energy in intramolecular natural energy decomposition analysis (INEDA) is divided into electrical, core, and charge transfer components. The INEDA method describes the fragments using the nonfragmented electronic density, and, therefore, there are no limitations in how to choose the boundary orbital. We used INEDA to evaluate the interaction energies that give origin to barriers of rotation around C C (C C ) and N C (N C ) bonds in arylamide-foldamer building blocks. We found that differences of barrier height between models with different ortho-aryl substituents stem from charge transfer and core interactions. In three-center hydrogen-bond (H-bond) models with an NH proton donor H-bound to two electronegative ortho-aryl substituents, the interaction energy of the three-center system is larger than in either of the two-center H-bond subsystem alone, indicating an increase of overall rigidity. The combination of INEDA and NEDA allows the evaluation of intermolecular and intramolecular interactions using a consistent theoretical framework. © 2018 Wiley Periodicals, Inc.