Abstract
Rotational spectroscopy has long been used for the study of small molecule chemical structure and has only recently found its way into the field of analytical chemistry for larger and more complex molecules. The development of the Fabry-Pérot cavity Fourier transform microwave spectrometer with a pulsed molecular beam source [1] allowed for the study of larger molecules and weakly bound clusters of molecules; however, this instrument required stepping through a frequency space over large lengths of time with continuous measurements lasting hours to days to acquire a broadband spectrum [2]. It was the invention of chirped-pulse Fourier transform microwave (CP-FTMW) spectroscopy in 2006-2008 [3,4] that allowed for acquisition of broadband spectra with high spectral resolution in a factor of >1000 less time and that contains spectral signatures of many species at once. With improvements to the technology backing this instrumentation, complex chemical mixtures containing structural isomers, regioisomers, diastereomers, isotopologues and isotopomers, conformers, and minor impurities can be analyzed without separation techniques making the technique advantageous to pharmaceutical synthetic processes and even real-time quality assurance [5, 6, 7]. More recently, rotational spectroscopy has also shown its ability in distinguishing enantiomers and quantifying enantiomeric excess through microwave three-wave mixing (3WM) rotational spectroscopy [8] and chiral tag rotational spectroscopy [9].
This dissertation will show how challenging chemical mixtures in a wide array of settings in the analytical field are easily analyzed by the new techniques in rotational spectroscopy. The quantitative limits in determining enantiomeric excess by 3WM rotational spectroscopy will be discussed including the technique’s strength in complex mixtures through analysis of components in essential oil mixtures. An additional project will be discussed in which 3WM rotational spectroscopy is used as a technique in designing an instrument for prospective use in biomarker detection in the search of past or present life in various locations within the solar system. In another group of projects, The CP-FTMW instrument is used to show how isotopic impurity levels in the synthesis of deuterated molecules can be quickly analyzed through the use of ‘cocktail’ reaction mixture analysis. Additional mixture analysis will be shown on deuterated molecules used in a building block strategy for drug design in which quick, quantitative analysis in a new sampling system guides synthetic chemists to produce targets with lower abundances of impurities. This final project includes using the chiral tag rotational spectroscopy technique to determine the enantiomeric excess and absolute configuration of a molecule that is chiral merely by deuterium substitution, showing the strength of rotational spectroscopy in sensing the smallest of structural changes.
[1] Balle, T. J.; Flygare, W. H., Fabry–Perot cavity pulsed Fourier transform microwave spectrometer with a pulsed nozzle particle source. Review of Scientific Instruments 1981, 52 (1), 33-45.
[2] Park, G. B.; Field, R. W., Perspective: The first ten years of broadband chirped pulse Fourier transform microwave spectroscopy. J Chem Phys 2016, 144 (20), 200901.
[3] Brown, G. G.; Dian, B. C.; Douglass, K. O.; Geyer, S. M.; Pate, B. H., The rotational spectrum of epifluorohydrin measured by chirped-pulse Fourier transform microwave spectroscopy. Journal of Molecular Spectroscopy 2006, 238 (2), 200-212.
[4] Brown, G. G.; Dian, B. C.; Douglass, K. O.; Geyer, S. M.; Shipman, S. T.; Pate, B. H., A broadband Fourier transform microwave spectrometer based on chirped pulse excitation. Rev Sci Instrum 2008, 79 (5), 053103.
[5] Neill, J. L.; Yang, Y.; Muckle, M. T.; Reynolds, R. L.; Evangelisti, L.; Sonstrom, R. E.; Pate, B. H.; Gupton, B. F., Online Stereochemical Process Monitoring by Molecular Rotational Resonance Spectroscopy. Organic Process Research & Development 2019, 23 (5), 1046-1051.
[6] Vang, Z. P.; Reyes, A.; Sonstrom, R. E.; Holdren, M. S.; Sloane, S. E.; Alansari, I. Y.; Neill, J. L.; Pate, B. H.; Clark, J. R., Copper-Catalyzed Transfer Hydrodeuteration of Aryl Alkenes with Quantitative Isotopomer Purity Analysis by Molecular Rotational Resonance Spectroscopy. J Am Chem Soc 2021, 143 (20), 7707-7718.
[7] Smith, J. A.; Wilson, K. B.; Sonstrom, R. E.; Kelleher, P. J.; Welch, K. D.; Pert, E. K.; Westendorff, K. S.; Dickie, D. A.; Wang, X.; Pate, B. H.; Harman, W. D., Preparation of cyclohexene isotopologues and stereoisotopomers from benzene. Nature 2020, 581 (7808), 288-293.
[8] Patterson, D.; Doyle, J. M., Sensitive chiral analysis via microwave three-wave mixing. Phys Rev Lett 2013, 111 (2), 023008.
[9] Brooks H. Pate, L. E., Walther Caminati, Yunjie Xu, Javix Thomas, David Patterson, Cristobal Perez, Melanie Schnell, Quantitative Chiral Analysis by Molecular Rotational Spectroscopy. In Chiral Analysis, 2 ed.; 2018; pp 679-729.
