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

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 C α −CO and the C α −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 Δδ RS 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 Δδ RS 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.