The conformational diastereomers of 5-substituted-5H-6-chlorodibenzo[a,c]cycloheptene

Abstract

Conformational diastereomers of 5-substituted-5H-6-chlorodibenzo[a,c]cycloheptene 1 are observed at room temperature in solution. Empirical force field and the AM1 semi-empirical quantum mechanics calculations indicate that the conformation of the cycloheptatriene ring in 1 is a boat (B) form. In the B form, the C-5 substituent can be oriented in equatorial (e) and axial (a) directions. The e–a interchange involves inversion of the biphenyl moiety in the range of 14.1–17.7 kcal mol⁻¹, determined by ¹H-NMR band shape analysis. The free energy difference between the e–a forms is not reproduced by the AM1 calculations. The e–a equilibrium in derivatives of 1 depend on the solvent polarity: for 1i the e–a ratio in CDCl₃ (28 ∶ 72) changes to (55 ∶ 45) in DMSO-d₆.The conformational space of the flexible side chains in all mono-substituted compounds except 1k is searched by molecular mechanics and the AM1 semi-empirical method and the relative heats of formation of all rotamers are considered in estimation of the e–a ratio. Many of the rotamers show an internal hydrogen bond calculated by the AM1 method. The diethylamino derivative of 1 (1l) was found just in the e form. The preferred conformation of 1h in the solid state was found by X-ray crystallography of a single crystal to be e with a strong OH⋯N internal hydrogen bond in the side chain. Dissolution of the 1h single crystals at low temperature and recording the ¹H-NMR spectrum at −60 °C show that assignment of the e form as the dominant one at room temperature for 1h is justified.