Synthesis and dynamics of atropisomeric (S)-N-(α-phenylethyl)benzamides

The synthesis of atropisomeric 2-substituted benzamides 2a–e, 3a–e, and 4a–e, and characterization by X-ray structure analysis of 2d, 2e, 3c, 3e, 4c, and 4e are reported. Dynamic 1H NMR spectroscopic studies of benzamides 2b–d, 3b–d, and 4b–d indicate that only two of the four possible rotamers are present in solution, with population ratios ranging between 1.5:1 and 4.1:1. The measured free energy of activation to interconversion of the rotamers ranged from 12.4 to 18.9 kcal mol−1. Benzamides ArCON[(S)-phenethyl]2 (2e, 3e, and 4e), exhibited atropisomer ratios between 1.7:1 and 1:1, and free energies of interconversion of the rotamers ranged from 11.5 to 17.6 kcal mol−1. The highest rotation barriers were observed for the ortho-nitro derivatives 2a–e. Molecular calculations at the semiempirical level (PM3MM) gave free energies of activation for benzamides 2e and 3e of 23.6 and 12.4 kcal mol−1, respectively, which are comparable to the experimental values.