Conformational analysis of menthol diastereomers by NMR and DFT computation

Correlations between experimental and calculated 13C chemical shifts were performed with the series of all menthol diastereomers. In this way it could be shown that identification problems with newly isolated natural products can be solved. Starting from simulated, low energy conformers of menthol, neomenthol, isomenthol, and neoisomenthol the 13C chemical shifts were obtained using DFT calculations [functional: B3LYP, basis set: 6-31G(d,p)]. Due to differences in chemical shifts, the prochiral methyl groups of the isopropyl substituent of menthol could be differentiated using the correlations between experimental and calculated values. A conformational scan of the dihedral angle of the isopropyl group allowed the determination of the dominating rotamers of menthol (+68.4°) and neomenthol (+172.5°) using 13C chemical shifts. The results were supported by energy calculations, 1JCH and 3JHH measurements. The correlations and 3JHH measurements for isomenthol indicate conformational averaging impeding the determination of the isopropyl group rotamer. For neoisomenthol, MD simulations showed two chair conformations. However, in contrast to calculated energies and correlations between theoretical and experimental 13C chemical shifts, the measured 3JH3H2 coupling of 6.3 Hz indicates an equally populated equilibrium of both conformers.