Chiral analysis was performed on samples of isopulegol and its isomers using chiral tag rotational spectroscopy. Isopulegol, with three chiral centers, has 8 stereoisomers. There are four diastereomers with distinct geometries and the diastereomer ratio can be determined using traditional rotational spectroscopy. To determine the enantiomeric ratio for each diastereomer the chiral tagging method was used to convert these enantiomers into distinguishable diastereomer complexes. Isopulegol was placed into the nozzles of a chirped-pulsed Fourier transform microwave spectrometer and was heated to 323K. The isopulegol was complexed with a 0.1% mixture of propylene oxide in neon as the carrier gas. The measurement methodology for EE determinations is: 1) a 400K average spectrum is measured using the enantiopure S-propylene oxide, 2) the tag is purged by flowing pure neon over the sample and heating, and 3) a 400K average spectrum using racemic propylene oxide is measured. Enantiopure samples of (-)-isopulegol and (+)-isopuelgol were purchased from Sigma Aldrich and used to create standards of 0, 5, 10, 30, 55, 80, and 90 enantiomeric excess of (-)-isopulegol. The calibration curve was fit using a linear expression with zero offset giving a slope of 1.005 ± 0.007 (R 2 = 0.99935). These results demonstrate that the method has linear performance over the full EE scale. The reference solution with EE=80 was measured in six separate runs to assess reproducibility. The average of the measurements was 80.595% with a standard deviation of 0.274. A sample of isopulegol provided as a mixture of isomers (Alfa Aesar) was analyzed using the chiral tag method. The enantiomeric excess for the two most abundant diastereomers were determined: isopulegol: EE=4.1(4) and neoisopulegol: EE=4.8(4). The similar enantiomeric excess values for these isomers is consistent with the usual production method for isopulegol where the EE of the reagent (citronellal) sets the EE for all four diastereomer products.
Chiral tag rotational spectroscopy can be used for quantitative determination of the ratio of the two enantiomers of a chiral molecule. The strategy for chiral tag rotational spectroscopy is to convert the enantiomers of the analyte into diastereomers through non-covalent attachment of a small, chiral tag molecule. The analyte enantiomer ratio, which is used to determine the enantiomeric excess (EE), is determined by comparing the transition intensities of rotational transitions for the homochiral and heterochiral complexes when both a racemic and enantiopure tag sample is used. A calibration curve for EE determination of 3-methylcyclohexanone tagged with 3-butyn-2-ol will be presented. The role that intensity fluctuations in back-to-back measurements of the rotational spectra of the chiral tag complexes play in determining the EE measurement accuracy will be described. In applications to pharmaceutical chemistry the main need is the ability make quantitative EE determinations in the high enantiopurity limit of the analyte. This requirement poses challenges for chiral tag rotational spectroscopy from both the measurement sensitivity and the availability of high enantiopurity tag samples. Two analysis methods for high EE measurements will be discussed. In one case, the enantioimpurity detection limit is decreased by the co-adding of multiple rotational transitions of the homochiral and heterochiral tag complex. The second strategy uses a lower enantioimpurity tag to speed the EE determination of high enantioimpurity samples. In this case, the ability to accurately determine the tag EE is crucial and the functional dependence of EE measurement precision in chiral tag rotational spectroscopy provides the limit on measurement accuracy that can be achieved.
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