Stereochemical analysis of menthol and menthylamine isomers using calculated and experimental optical rotation data

• The correct absolute configuration of 12 molecules could be predicted by experimental and calculated NMR and chiroptical data.
• For the first time, a conformational analysis of neoisomenthol was performed based on calculated and experimental chemical shifts.
• We found an incorrect assignment of menthylamine in the literature and revised it to neomenthylamine.
• We propose not to use experimental optical rotation values smaller than 10 for a reliable prediction of the absolute configuration.

The complete series of menthol isomers and their corresponding amino derivatives (base and protonated/HCl forms), were investigated using experimental and theoretical data. Our study focused on the conformational and configurational analysis, and revealed that experimental data should be used in combination with calculated data. Furthermore, even in the case of the highly studied member, menthol, discrepancies were found among previously published literature values. We show that the correct determination of the population mix is a must for the correct prediction of the absolute configuration (AC) of neoisomenthol. The neoiso forms are of special interest since a number of structural inconsistences can be found in the literature. We present a stringent proof of the AC of neoisomenthol based on literature information. To the best of our knowledge, the AC of neoisomenthylamine is for the first time shown using experimental and calculated optical rotation data. A correction of a series of publications containing an important error in the assignment of (+)-menthylamine (correct: (+)-neomenthylamine) is presented. With 26 data pairs (experimental versus calculated) of optical rotation values a regression is performed. The AC of all 12 compounds, even the most difficult neoiso forms, could be predicted correctly using experimental low-temperature NMR data. Furthermore, if only experimental data with an optical rotation outside the range of −10 < [α] > +10 are used, all 12 compounds would have been correctly assigned without low-temperature NMR data as restraints.

The complete series of menthol and menthylamine (base and protonated/HCl form) isomers has been investigated concerning their conformation and configuration. Using experimental and calculated optical rotation data it was possible to successfully assign the absolute configuration for all 12 compounds.Figure optionsDownload as PowerPoint slide