(3R,4S)-4-(4-Fluorophenyl)-3-hydroxymethyl-1-methylpiperidine: conformation and structure monitoring by vibrational circular dichroism

J Org Chem. 2002 Jan 11;67(1):161-8. doi: 10.1021/jo016094s.

Abstract

Absorption and vibrational circular dichroism (VCD) spectra of the title compound, a common intermediate in synthesis of many pharmaceuticals, were measured and analyzed in order to determine its absolute configuration and prevailing conformations. The analysis was combined with a systematic conformer search based on relative energies as well as with comparison of experimental and computed NMR shifts. The spectra were interpreted on the basis of ab initio simulations. The results indicate that the compound adopts exclusively a chair conformation of the piperidine ring with all the fluorophenyl, hydroxymethyl, and methyl substituents attached in equatorial positions. A limited rotation of the hydroxymethyl group is most consistent with the observed VCD pattern. VCD parameters were found significantly more sensitive to conformational changes than absorption or NMR. Concentration dependence of the absorption spectra indicated aggregation in concentrated solutions, but involved hydrogen bonds probably do not influence molecular conformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Circular Dichroism
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Piperidines / chemistry*
  • Spectroscopy, Fourier Transform Infrared
  • Static Electricity
  • Stereoisomerism
  • Vibration

Substances

  • Piperidines