Chiral Analysis by Chiral Tag Rotational Spectroscopy

Chiral compounds are of immense importance for medicinal research and pharmaceutical manufacturing. A complete chiral analysis would quantify all stereoisomers of a molecule which scales by 2N, where N is the number of chiral centers. There are 2N-1 diastereomers and for each diastereomer there is an enantiomer. Furthermore, the analysis would allow for quantification of the enantiomeric excess, EE, of each component. This dissertation presents the ability of chiral tag rotational spectroscopy for chiral analysis.

In traditional rotational spectroscopy, enantiomers of a molecule have identical rotational spectra, but diastereomers have unique rotational spectra. Chiral tag rotational spectroscopy works by the addition of a new, known chiral center onto a chiral molecule thereby converting enantiomers into diastereomers. The new stereocenter is added through non-covalently complexation with a small chiral molecule designated a “chiral tag”. Complexation is achieved through the use of seeded molecular beams and are measured using a chirped-pulse Fourier transform microwave (CP-FTMW) spectrometer.

The first component of chiral analysis is the determination of enantiomeric excess in a sample. Since the enantiomers are turned into diastereomeric complexes, the rotational spectra for both are now distinguishable. However, due to the nature of the rotational measurements, the signal levels of the different transitions need to be normalized, which is accomplished through the measurement with a racemic form of the tag. An enantiopure form of the tag is then used and a ratio of the signal levels, after being normalized, is used to calculate an enantiomeric excess. As many rotational transitions are observed in a rotational spectrum, many enantiomeric excess calculations may be made for improved accuracy and error estimation.

The last component of chiral analysis is the determination of absolute configuration. In chiral tag rotational spectroscopy, the measurement using the racemic tag allows observation of both diastereomeric complexes. In the enantiopure tag spectrum, one of these complexes is reduced in signal intensity, while the other is increased, if the sample is not racemic. This separates the rotational spectra into two distinct groups, which are then assigned by comparison of their rotational constants to rotational constants theoretically calculated using computational quantum chemistry. The accuracy of these methods for absolute configuration assignments is explored, and the ability for high-confidence assignment through comparison of atomic coordinates using Kraitchman’s equations.