Choosing the Right Reagent for the Determination of the Absolute Configuration of Amines by NMR: MTPA or MPA?

Abstract

Molecular mechanics, semiempirical (AM1), aromatic shielding effect calculations, and dynamic NMR experiments demonstrate that MTPA amides are constituted by three main conformers, sp, ap3, and ap1 due to restricted rotation around the Cα−CO and the Cα−Ph bonds. Unlike MTPA esters, where the three rotamers have almost identical populations, in MTPA amides rotamer sp is more populated than the other two and has a shielding rather than deshielding character. This produces larger ΔδRS values for MTPA amides than for MTPA esters. Therefore, inference of absolute configuration with this reagent should be correspondingly more reliable for amines than for alcohols. Assignment of absolute configuration of chiral primary α-substituted amines with MTPA gives similar ΔδRS values than with MPA. A graphical description of the aromatic magnetic field distribution in MTPA and MPA amides, and its use to correlate the average chemical shifts with the absolute configuration of the amine, is presented.