Propylene oxide (PO), a simple chiral cyclic ether, has served as a valuable prototype molecule for the theoretical development of chiroptical activities and for rotational spectroscopic studies of chirality recognition . Although a rotational spectroscopic study of the PO dimer was completed more than ten years ago where six homo- and heterochiral structures were identified experimentally3, no similar studies of larger chiral aggregates such as a PO trimer have been reported so far. This is in part because the conformational ensemble space grows exponentially as the size of aggregates increases, making it highly challenging to detect and assign the related rotational spectra. Aided with the recent development in chirped pulse Fourier transform microwave techniques and in meta-dynamics conformational search algorithms , we have explored the conformational space of the PO trimer. Several hundred possible PO trimer structures were predicted the first two most stable homochiral trimers were assigned. The number of possible conformers of the heterochiral PO trimer predicted is about three times of that of the homochiral trimer. Even so, no match could be made for the heterochiral trimer conformers detected, despite additional exhausted conformational searches. By studying all monosubstituted 13C isotopologues of the most stable homochiral and heterochiral PO trimer in nature abundance, we experimentally determined their C atom backbone structures. Guided with this information, additional PO trimer structures were calculated which match the observed rotational constants and dipole moments. The study showcases the power current rotational spectroscopic experiments and highlights the necessity of intensive interplay between experiment and theory in dealing with large aggregates (or molecules). Interesting results on chirality recognition in the PO trimer will also be discussed. 1.R. W. Kawiecki, F. J. Devlin, P. J. Stephens, R. D. Amos, J. Phys. Chem. 1991, 95, 9817. 2.Z. Su, N. Borho, Y. Xu. J. Am. Chem. Soc. 2006, 128, 51. 3.G. Barratt Park, and Robert W. Field, J. Chem. Phys. 2016, 144, 20090. 4.P. Pracht, F. Bohle and S. Grimme, Phys. Chem. Chem. Phys., 2020.

Density functional theory is used to examine the possible conformations of both homochiral (RR or SS) and heterochiral (RS or SR) homodimers of 3,3-difluoro-1,2-epoxypropane and 3-fluoro-1,2-epoxypropane as a guide in the search for their microwave spectra. Similar to the analogous homodimers of 3,3,3-trifluoro-1,2-epoxypropane, the lowest energy heterochiral dimers of these species contain an inversion center and are microwave silent. However, spectra are obtained for the lowest energy conformers of the homochiral dimers. Analysis of the spectra confirms the theoretically predicted geometries.

Building off the previous works of Schnell, Patterson, and Pate, a new microwave three-wave mixing (M3WM) spectrometer was constructed and tested at the Missouri University of Science and Technology. This new instrument consists of a four-horn design, allowing traditional CP-FTMW experiments to be performed in addition to M3WM experiments. Within this presentation, the design, construction, and demonstration of the instrument's capabilities using 2-bromo-1,1,1,2-tetrafluoroethane will be discussed. Preliminary work on chirality detection and dipole forbidden transition analysis utilizing M3WM techniques will also briefly be presented.

Microwave three-wave mixing, which was first demonstrated in 2013 by Patterson, Schnell, and Doyle [1, 2] and described eloquently in NMR terminology by Grabow [3], has shown its applicability in differentiating enantiomers as well as quantifying enantiomeric excess for chiral molecules in the gas phase. Further theoretical development of rotational three-wave mixing has been presented by Lehmann. [4] However, this technique’s capability has not been fully explored and the sensitivity of different measurement implementations have not been evaluated. This work presents a simplified measurement scheme in which two high-frequency (4-12 GHz) transitions of a chiral gas sample are excited with orthogonally polarized pulses of light utilizing a dual-polarization wave horn antenna. The low-frequency chiral emission signal (600-2000 MHz) is detected at the mutually orthogonal polarization and perpendicular to the excitation pulse propagation direction. In this measurement scheme, the detection electronics and digitization rate required are simplified and reduced. Propylene oxide, alanine, and menthone introduced in a pulsed-jet expansion are used to demonstrate the low-frequency detection method and its comparison to traditional three-wave mixing schemes where detection of a high-frequency signal is employed. Additionally, some other nuances of the measurement technique have been explored including the angular dependence of the chiral emission and the importance of the polarization in the excitation and detection horn antennae. [1] D. Patterson, M. Schnell, and J.M. Doyle, “Enantiomer-specific detection of chiral molecules via microwave spectroscopy”, Nature 497, 475-478 (2013). [2] D. Patterson and J.M. Doyle, “Sensitive Chiral Analysis via Microwave Three-Wave Mixing”, Phys. Rev. Lett. 111, 023008 (2013). [3] J. Grabow, “Fourier Transform Microwave Spectroscopy: Handedness Caught by Rotational Coherence”, Angew. Chem. Int. Ed. 52, 11698-11700 (2013). [4] K.K. Lehmann, “Theory of Enantiomer-Specific Microwave Spectroscopy”, in Frontiers and Advances in Molecular Spectroscopy, 713-743 (2018).

Chiral analysis, the determination of the absolute configuration of a chiral molecule and its enantiomeric excess, is a challenging analytical chemistry problem. Rotational spectroscopy can perform chiral analysis through either three-wave mixing spectroscopy, as introduced into the field by Patterson, Doyle, and Schnell, or through the chiral tag method. In chiral tagging, a small, chiral molecule serves as the chiral resolving agent and is attached to the analyte through noncovalent interactions. This work considers suitable tags to perform chiral analysis on carboxylic acids. 2-phenylpropionic acid was used to illustrate the proof-of-principle for chiral analysis of carboxylic acids using propylene oxide and butynol as the chiral resolving agent. Propylene oxide is found to have a functional group specific binding motif. Candidate chiral tag complex structures were evaluated using DFT calculations (B3LYP GD3BJ def2TZVP). The presence of these complexes in the pulsed jet sample were verified by comparison between experimental and theoretical rotational constants. Chiral tag measurements with propylene oxide pose a challenge because there are geometries for homochiral and heterochiral complexes with nearly identical rotational constants and dipole moment components. The close similarity makes it difficult to determine the absolute configuration to high confidence. However, the tag complexes of similar geometry have different relative energies for homochiral and heterochiral interactions. The lower energy conformers were more likely to be observed, indicating efficient cooling in the jet pulse. In this case, it appears that energetic considerations can be used to establish the absolute configuration. Methodology and analysis, as well as C¹³ structure fits and EE determination, will be further discussed.

In the course of measurements to develop a chiral tag rotational spectroscopy methodology for establishing the absolute configuration of fluorinated carboxylic acids, an interesting reaction chemistry was found. In most cases, fluorinated carboxylic acids undergo ring opening of epoxides under ambient conditions. Reactions of four fluorinated carboxylic acids, difluoroacetic acid, trifluoroacetic acid, and pentafluoropropionic acid, with propylene oxide (PO) were explored. The reactions were performed externally to the spectrometer and internally in the gas phase by flowing PO over the fluorinated acid samples. External reactions were performed by adding volumetric amounts of PO with each carboxylic acid in a 4:1 molar ratio. The reactions were highly exothermic. The reaction mixtures were analyzed by rotational spectroscopy using a chirped-pulsed Fourier transform rotational spectrometer. These measurements showed that the reaction products are created through epoxide ring-opening at both epoxide ring carbons. This reaction chemistry, in principle, offers a way to perform chiral analysis through covalent tagging, but this application would require retention of configuration in the reaction. The reaction products were subsequently chiral tagged to determine the extent of configuration retention. These experiments show that partial retention of configuration is achieved. The scope of reaction was further explored using trifluoropropylene oxide and styrene oxide. Using trifluoropropylene oxide no reaction or reaction products were observed. Styrene oxide produced epoxide ring-opening products both at most- and least-substituted carbon. In contrast to propylene oxide, only one conformer was observed for the reaction product of the fluorinated acids and styrene oxide.

In the search for life elsewhere in our solar system, the development of tools to measure key biomarkers is a critical area of research. One biomarker found in nature on Earth is homochirality, the predominant utilization of one handedness (enantiomer) of a biological chiral molecule over another. For example, the biological prevalence of left-handed amino acids and right-handed sugars. Developing compact, low-power instruments to detect important chiral biomolecules and measure their enantiomeric excess with high sensitivity is a challenge. We are developing and testing the three-wave mixing technique for rotational spectroscopy which was demonstrated in 2013 [1, 2] to meet these challenges. The instrument can perform sensitive detection when operated as a traditional rotational spectrometer and subsequently perform chiral measurements (absolute configuration and the enantiomeric excess) by three-wave mixing without the need for derivatizing agents or prior separation of mixtures. We use W-band (70-90 GHz) and centimeter-wave (2-8 GHz) excitation sources to excite a small amount (3-5 mTorr) of gas phase chiral molecules and generate a chiral free-induction decay in the W-band. Propylene oxide is used as the test-case molecule and chiral emission is detected for its R-and S-forms with 180 degrees phase shift allowing us to differentiate the two enantiomers. The use of millimeter-wave technology in the instrument design provides a path to future reductions in size, weight, and power of the ChiralSpec instrument that make it compatible with the stringent requirements of space missions. [1] D. Patterson, M. Schnell, and J.M. Doyle, “Enantiomer-specific detection of chiral molecules via microwave spectroscopy”, Nature 497, 475-478 (2013). [2] D. Patterson and J.M. Doyle, “Sensitive Chiral Analysis via Microwave Three-Wave Mixing”, Phys. Rev. Lett. 111, 023008 (2013).

Over the last few years, microwave three-wave mixing (M3WM) experiments have emerged as a sensitive tool to measure enantiomer-specific molecular signals in the microwave regime.Patterson, D.; Schnell, M.; Doyle, J. M. Enantiomer-Specific Detection of Chiral Molecules via Microwave Spectroscopy. Nature 2013, 497, 475-477.^,Patterson, D.; Doyle, J. M. Sensitive Chiral Analysis via Microwave Three−Wave Mixing. Phys. Rev. Lett. 2013, 111, 023008.ontrol over the relative phases and polarizations of applied excitation pulses provides a way to selectively populate or depopulate a particular rotational state to create an enatiomeric enrichment through selective population transfer.Eibenberger, S.; Doyle, J.; Patterson, D. Enantiomer−Specific State Transfer of Chiral Molecules. Phys. Rev. Lett. 2017, 118, 123002.^,Perez, C.; Steber, A. L.; Domingos, S. R.; Krin, A.; Schmitz, D.; Schnell, M. Coherent Enantiomer-Selective Population Enrichment Using Tailored Microwave Fields. Angew. Chem. Int. Ed. 2017, 56, 12512–12517.his approach has been demostrated in systems with a stereogenic center, where the two enantiomers are separated by an infinitly high barrier. In this talk, we will present succesful population transfer experiments on systems that do not have a stereogenic center but may become chiral due to their three-dimensional arrangement upon cooling, such as chiral conformers.Perez, C., Steber, A. L., Krin, A., Schnell, M. (2018). State-Specific Enrichment of Chiral Conformers with Microwave Spectroscopy. The Journal of Physical Chemistry Letters, 9(16), 4539n these kinds of systems, the enantiomeric pair is separated by an relatively high barrier that cannot be overcome to enable interconversion on the timescale of the experiment. When the barrier is lowered further, quantum tunneling is usually observed in the microwave spectrum. We will show that it is possible to perform M3WM and population enrichment experiments in this kind of systems. The experimental implementation will be presented and discussed.

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Footnotes:

Patterson, D.; Schnell, M.; Doyle, J. M. Enantiomer-Specific Detection of Chiral Molecules via Microwave Spectroscopy. Nature 2013, 497, 475-477.\end Patterson, D.; Doyle, J. M. Sensitive Chiral Analysis via Microwave Three−Wave Mixing. Phys. Rev. Lett. 2013, 111, 023008.C\end Eibenberger, S.; Doyle, J.; Patterson, D. Enantiomer−Specific State Transfer of Chiral Molecules. Phys. Rev. Lett. 2017, 118, 123002. Perez, C.; Steber, A. L.; Domingos, S. R.; Krin, A.; Schmitz, D.; Schnell, M. Coherent Enantiomer-Selective Population Enrichment Using Tailored Microwave Fields. Angew. Chem. Int. Ed. 2017, 56, 12512–12517.T Perez, C., Steber, A. L., Krin, A., Schnell, M. (2018). State-Specific Enrichment of Chiral Conformers with Microwave Spectroscopy. The Journal of Physical Chemistry Letters, 9(16), 4539I