Amide bond modulation: partial amide bond rotation in cyclic amines of DEET analogs follow an enthalpy-entropy compensation (EEC)

Recently, studies using nuclear magnetic resonance (NMR) spectroscopy on analogs of the pest repellent m-DEET have shown that a third higher energy trapped conformation exists with some ortho substitutions and is evident as the third set of methylene peaks in the 3.4-3.6ppm chemical shift range. Further, studies have also shown that DEET’s amide bond has the potential to be altered by electronic and steric interactions. Based on these findings, we explore further thermodynamic insight that can be gained by altering the size and magnitude of electron withdrawing/donating aromatic substituents in combination with cyclic amines. Our long-term goal is to understand how thermodynamic principles affect amide bond rotation and use this information toward improving DEET’s ligand efficiency as an odorant. Eyring analysis of variable temperature NMR spectra suggests that enthalpy and entropy of the transition state for all 48 analogs synthesized follows an enthalpy-entropy compensation (EEC) mechanism and limited to a relatively small window of Gibbs energy of the transition state. Using an EEC plot gives a better idea as to how changes to DEET’s structure alter the Gibbs energy of the transition state.