SAMPLING REQUIREMENTS FOR MIXTURE ANALYSIS USING MOLECULAR ROTATIONAL RESONANCE SPECTROSCOPY

Over the past few years, a number of studies have been performed that show the capability for gas-phase molecular rotational spectroscopy to perform quantitative mixture analysis. In particular, the ability of this technique to identify new compounds in a mixture on the basis of comparison to electronic structure theory is extremely powerful. For a number of reasons, however, the sample introduction and volatilization methods employed warrant new development. First, mixtures often contain components with different vapor pressures, and so care is required in extrapolating concentration information from observed signals.\footnote{C. West \textit{et al.}, "Analysis of pear ester flavoring samples using broadband rotational spectroscopy," 2018 International Symposium on Molecular Spectroscopy, talk RH06.} Additionally, operator-to-operator variability, measurement cycle time, and ease of use are factors that should be considered. We will discuss our efforts to develop sampling interfaces to enable routine quantitative mixture analysis using molecular rotational spectroscopy, as well as challenges that the field still faces

STEREOCHEMICAL IDENTIFICATION OF AN INTERMEDIATE IN THE SYNTHESIS OF DOLUTEGRAVIR USING MOLECULAR ROTATIONAL RESONANCE SPECTROSCOPY

Over half of pharmaceuticals, both among the top 100 drugs by prescription totals and new U.S. Food and Drug Administration (FDA) approvals, contain at least one chiral center. Moreover, most new chiral pharmaceuticals are synthesized as a single isomer. Therefore, it is important to be able to determine the primary isomer generated by a synthetic process as well as the presence of any other isomers - preferably directly on the intermediate compounds where each chiral center has been introduced. Molecular rotational spectroscopy, with its sensitivity to small changes in structure and ability to identify compounds directly from electronic structure theory, can be a powerful tool in this application. The present study concerns dolutegravir, an HIV integrase inhibitor developed by GlaxoSmithKline and approved by the FDA in 2013. Efforts are ongoing at the Medicines for All institute in Richmond, Virginia to develop a stereoselective flow synthesis for dolutegravir to reduce its cost and increase availability.\footnote{R.E. Ziegler, B.K. Desai, J.-A. Jee, B.F. Gupton, T.D. Roper, and T.F. Jamison, \textit{Angew. Chem. Int. Ed.}, \textbf{2018}, \textit{130}, 7299-7303.} As part of a new route development, an intermediate with two chiral centers was assessed by rotational spectroscopy to determine which diastereomer was the predominant one formed by the process. Notably, NMR was unable to conclusively determine this, but rotational spectroscopy unambiguously determined that the synthetic route produced the correct stereochemistry. This result suggests that rotational spectroscopy can be a useful complement to other analytical characterization methods in organic process development

Frequency band performance comparisons for room-temperature chirped pulse millimeter wave spectroscopy

We present a performance comparison between chirped pulse millimeter wave spectrometers operating over 75-110, 260-290, and 520-580 GHz. For molecules at room temperature, the line strength has an approximately $\nu^3$ dependence until the peak of the Boltzmann distribution (typically in the submillimeter) is reached. However, we find competitive performance for 75-110 GHz spectrometers--with an average sensitivity drop of approximately 3-5 in equal measurement time, compared to a 260-290 GHz instrument with the same excitation power and measurement cell length. The narrower linewidth and lower line density at lower frequency, moreover, increase the usable dynamic range at 75-110 GHz by a factor of approximately 3-10 before reaching the confusion limit, giving better performance for extracting weak lines in a strong forest. This talk will discuss the reasons for and implications of these differences in performance for applications of chirped pulse millimeter wave spectroscopy

FAST CHIRAL MONITORING IN A CONTINUOUS PHARMACEUTICAL SYNTHESIS BY MOLECULAR ROTATIONAL RESONANCE SPECTROSCOPY

We present the successful application of MRR spectroscopy in the microwave region to monitor the output of a continuous pharmaceutical synthesis. Microwave spectroscopy has an excellent capability to distinguish isomers and other structurally similar compounds, and techniques have been developed recently that are also sensitive to enantiomeric excess. A Balle-Flygare-style Fourier transform microwave spectrometer was employed as the detector in this study, along with a new solutions sampling interface that injects crude product solution directly from the reactor, bakes off the solvent, and volatilizes the analyte mixture for analysis. The reaction under study was the catalytic asymmetric hydrogenation of artemisinic acid to produce a stable intermediate in the synthesis of artemisinin, an important antimalarial. The instrument is fully automated and consumes less than 1 mg of analyte in order to analyze the composition of 4 species with a detection limit of approximately 75 ppmw in the solution: the starting material, desired product, epimer of the product, and an overreduction byproduct that is not readily detectable by HPLC or NMR. This talk will describe the results of this study and prospects for future application in pharmaceutical process development

CHIRAL PROCESS MONITORING USING FOURIER TRANSFORM MICROWAVE SPECTROSCOPY

We present the application of Fourier transform microwave (FTMW) spectroscopy in monitoring the chiral purity of components in a reaction mixture. This is of particular interest due to the increasing use of continuous pharmaceutical manufacturing processes, in which a number of attributes (including the chiral purity of the product) can change on short time scales. Therefore, new techniques that can accomplish this measurement rapidly are desired. The excellent specificity of FTMW spectroscopy, coupled with newly developed techniques for measuring enantiomeric excess in a mixture, have motivated this work._x000d_ _x000d_ In collaboration with B. Frank Gupton (Virginia Commonwealth University), we are testing this application first with the synthesis of artemisinin. Artemisinin, a common drug for malaria treatment, is of high global health interest and subject to supply shortages, and therefore a strong candidate for continuous manufacturing. It also has moderately high molecular weight (282 amu) and seven chiral centers, making it a good candidate to test the capabilities of FTMW spectroscopy. Using a miniature cavity-enhanced FTMW spectrometer design,footnote{R.D. Suenram, J.U. Grabow, A.Zuban, and I.Leonov, Rev. Sci. Instrum. 70, 2127 (1999).} we aim to demonstrate selective component quantification in the reaction mixture. Future work that will be needed to fully realize this application will be discussed._x000d

ADVANCES IN MOLECULAR ROTATIONAL SPECTROSCOPY FOR APPLIED SCIENCE

Advances in chemical sensitivity and robust, solid-state designs for microwave/millimeter-wave instrumentation compel the expansion of molecular rotational spectroscopy as research tool into applied science. It is familiar to consider molecular rotational spectroscopy for air analysis. Those techniques for molecular rotational spectroscopy are included in our presentation of a more broad application space for materials analysis using Fourier Transform Molecular Rotational Resonance (FT-MRR) spectrometers. There are potentially transformative advantages for direct gas analysis of complex mixtures, determination of unknown evolved gases with parts per trillion detection limits in solid materials, and unambiguous chiral determination. The introduction of FT-MRR as an alternative detection principle for analytical chemistry has created a ripe research space for the development of new analytical methods and sampling equipment to fully enable FT-MRR. We present the current state of purpose-built FT-MRR instrumentation and the latest application measurements that make use of new sampling methods

Herschel observations of EXtra-Ordinary Sources: Analysis of the HIFI 1.2 THz Wide Spectral Survey Toward Orion KL II. Chemical Implications

We present chemical implications arising from spectral models fit to the Herschel/HIFI spectral survey toward the Orion Kleinmann-Low nebula (Orion KL). We focus our discussion on the eight complex organics detected within the HIFI survey utilizing a novel technique to identify those molecules emitting in the hottest gas. In particular, we find the complex nitrogen bearing species CH$_{3}$CN, C$_{2}$H$_{3}$CN, C$_{2}$H$_{5}$CN, and NH$_{2}$CHO systematically trace hotter gas than the oxygen bearing organics CH$_{3}$OH, C$_{2}$H$_{5}$OH, CH$_{3}$OCH$_{3}$, and CH$_{3}$OCHO, which do not contain nitrogen. If these complex species form predominantly on grain surfaces, this may indicate N-bearing organics are more difficult to remove from grain surfaces than O-bearing species. Another possibility is that hot (T$_{\rm kin}$$\sim$300 K) gas phase chemistry naturally produces higher complex cyanide abundances while suppressing the formation of O-bearing complex organics. We compare our derived rotation temperatures and molecular abundances to chemical models, which include gas-phase and grain surface pathways. Abundances for a majority of the detected complex organics can be reproduced over timescales $\gtrsim$ 10$^{5}$ years, with several species being under predicted by less than 3$\sigma$. Derived rotation temperatures for most organics, furthermore, agree reasonably well with the predicted temperatures at peak abundance. We also find that sulfur bearing molecules which also contain oxygen (i.e. SO, SO$_{2}$, and OCS) tend to probe the hottest gas toward Orion KL indicating the formation pathways for these species are most efficient at high temperatures.Comment: 31 pages, 6 figures, 1 Table, accepted to the Astrophysical Journa