Enantiomers – Image | Mirror Image

Chirality has a huge impact on the chemistry of a molecule. Due to potentially different physiological effects, pharmaceutical compounds are often used as enantiomerically pure compounds. One enantiomer can act as a healing agent, the other might be toxic to humans. Crazy, right? It makes sense, if you think of how pharmaceuticals work in principle. They bind to receptors, which trigger something in the brain or somewhere else in the human body. These receptors have a special chemical specificity and only the active compounds fit and bind correctly with it. A receptor is a 3D body and thereby is dependent on the stereochemistry of the compounds.

In NMR spectroscopy, enantiomers give the exact same spectrum (¹H or heteronuclear) because the corresponding nuclei in both enantiomeric environments have the exact same electronic surrounding, resulting in the same chemical shift. There is a very elegant method to reveal enantiomers in NMR spectroscopy. With a chiral derivatizing agent (CDA) you can transform an enantiomer into a diastereomer. Diastereomers have different electronic structure and therefore can be distinguished with NMR spectroscopy. So, what you do is to find a chiral auxiliary to use it as a CDA to react with your compound of interest.

I found^[1] that both enantiomers of tartaric acid (1a/1b) react in an acid base process with (S)-1-phenylethlyamine (2) to form the salts 3a and 3b, respectively, which are diastereomers (scheme 1). This reaction can be done in an NMR tube and figure 1 shows the proton NMR spectrum of 3a and 3b in DMSO-d₆.

SCHEME 1. REACTION OF (S)-1-PHENYLETHYLAMINE (2) WITH D- AND L-TARTARIC ACID (1A AND 1B).^[1]

The CHOH singlet of the diastereomers 3a and 3b differ in its chemical shift by Δδ = |4.008 – 4.022| ppm = 0.014 ppm. The difference is not too immense, because we have only made a small change to the molecular structure, but now compare the 1D proton spectra of the enantiomers of tartaric acid 1a and 1b in figure 2.

FIGURE 1. 1D PROTON DATA FOR 3A (LEFT) AND 3B (RIGHT) 0.25M IN DMSO-D₆.

FIGURE 2. 1D PROTON DATA FOR 1A (LEFT) AND 1B (RIGHT) 0.23M IN DMSO-D₆.

Here, the singlet corresponding to the CH atoms differs only about Δδ = |4.311 – 4.312| ppm = 0.001 ppm, so technically both have the same chemical shift (which matches the theory). Also, the “wavy-ish” baseline is due to the broad OH protons.

So, this is an example of how to use a chiral substance to turn enantiomers into diastereomers in order to make the stereochemistry visible in NMR spectroscopy. It’s also possible to determine the enantiomeric excess just with NMR spectroscopy (see Amine Chiral Analyzers for example), but that will be a topic for another blog post.

References
^[1] L. Mei, S. Jie. J. Ying, Res. Chem. Intermed. 2010, 36, 227–236.