An evaluation of substituent effects on aromatic edge-to-face interactions and CF–π versus CH–π interactions using an imino torsion balance model

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A selection of imines derived from phenyl t-butyl ketones and substituted 2-phenylethylamines or phenylalanine exhibit slow rotation around the aryl–imino bond at ambient temperature, resulting in a large non-equivalence of the ortho hydrogens in the 1H NMR spectra. This facilitates assessment of aryl substituent effects on the face tilted-T CH–π interaction between a phenyl ring (A) on the imino carbon proximate to the terminal phenyl ring (B). Analysis of the marked temperature dependence of the chemical shift of the interacting ortho hydrogen affords estimates of the opposing enthalpic and entropic factors involved in the rapid equilibrium between the closed edge-to-face conformation and alternative open conformations devoid of a CH–π interaction while in solution. Above ca. 80 °C the entropy term (TΔS) cancels out the enthalpy (ΔH) favouring the closed conformation and open conformations are preferred. Accordingly, commonly reported binding free energies may not be a good measure of the energetic strength of intramolecular aromatic interactions. Investigation of an ortho fluoro substituted compound indicates that a CF–π interaction is at least 1.0 kcal mol−1 weaker in enthalpy than the CH–π interaction. Several X-ray crystal structures depicting an intramolecular edge-to-face interaction are presented.