Quantitative Analysis of Challenging Chemical Mixtures by Rotational Spectroscopy

Holdren, Martin, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Holdren, Martin, Chemistry, University of Virginia

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.

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[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.

PHD (Doctor of Philosophy)
Rotational Spectroscopy, Three-Wave Mixing, Isotopic Isomers, Instrumentation
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