Since 15 years, a new type of chiroptical effect has been the subject of a large array of both theoretical and experimental studies: Photoelectron Circular Dichroism (PECD) in the angular distribution of photoelectrons produced by CPL-ionization of pure enantiomers in the gas phase observed as a very intense (up to 35 %) forward/backward asymmetry with respect to the photon axis and which reveals the chirality of the molecule (configuration). PECD happens to be an orbital-specific, photon energy dependent effect and is a very subtle probe of the molecular potential being very sensitive to static molecular structures such as conformers, chemical substitution, clusters, as well as to vibrational motion, much more so than other observables in photoionization such as the cross section or the β asymmetry parameter (for a recent review see L. Nahon, G. A. Garcia, and I. Powis, J. Elec. Spec. Rel. Phen. 204, 322 (2015)). Therefore PECD studies have both a fundamental interest as well and analytical interest, especially since chiral species are ubiquitous in the biosphere, food and medical industry. This last aspect is probably the driving force for the recent extension of PECD studies by the laser community using UV REMPI schemes. After a large introduction to the PECD process itself, and a description of our double imaging electron/ion coincidence set-up, several recent results on one-photon VUV PECD will be presented, including: • Sensitivity to chemical substitutions, isomerism and conformation • Case of floppy biomolecules such as amino acids alanine and proline with a conformer analysis and possible consequences for the origin of life’s homochirality • Analytical capabilities in terms of enantiomeric excess determination on a pure molecule as well as on a mixture of compounds. Future trends for PECD studies will be given regarding the case of more complex/structured chiral systems as well as opportunities for time-resolved PECD opened by the recent first performance of PECD with fs HHG pulses and REMPI time-resolved PECD.

Essential oils, such as peppermint or pennyroyal oil, are widely used in medicine, pharmacology and cosmetics. Their major constituents, terpenes, are mostly chiral molecules and thus may exhibit different biological functionality with respect to their enantiomers. Here, we present recent results on the enantiomers of pulegone, one of the components of the peppermint (Mentha piperita L.) and pennyroyal (Mentha pulegium) essential oils, using the microwave three-wave mixing (M3WM) technique.
M3WM relies on the fact that the scalar triple product of the dipole moment components μ_a, μ_b and μ_c differs in sign between the enantiomers. A loop of three dipole-allowed rotational transitions is required for the analysis of a chiral molecule. Since the recorded signal will be exactly out of phase for the two enantiomers, an unambiguous differentiation between them is possible, even in complex mixtures.
In addition to the chiral analysis of pulegone, its internal dynamics, resulting from the independent rotation of two of its three methyl groups, will be discussed. Moreover, a cluster of pulegone with one water molecule will be presented.

The introduction of three wave mixing rotational spectroscopy by Patterson, Schnell, and Doyle [1,2] has expanded applications of molecular rotational spectroscopy into the field of chiral analysis. Chiral analysis of a molecule is the quantitative measurement of the relative abundances of all stereoisomers of the molecule and these include both diastereomers (with distinct molecular rotational spectra) and enantiomers (with equivalent molecular rotational spectra). This work adapts a common strategy in chiral analysis of enantiomers to molecular rotational spectroscopy. A “chiral tag” is attached to the molecule of interest by making a weakly bound complex in a pulsed jet expansion. When this tag molecule is enantiopure, it will create diastereomeric complexes with the two enantiomers of the molecule being analyzed and these can be differentiated by molecule rotational spectroscopy. Identifying the structure of this complex, with knowledge of the absolute configuration of the tag, establishes the absolute configuration of the molecule of interest. Furthermore, the diastereomer complex spectra can be used to determine the enantiomeric excess of the sample. The ability to perform chiral analysis will be illustrated by a study of solketal using propylene oxide as the tag. The possibility of using current methods of quantum chemistry to assign a specific structure to the chiral tag complex will be discussed. Finally, chiral tag rotational spectroscopy offers a “gold standard” method for determining the absolute configuration of the molecule through determination of the substitution structure of the complex. When this measurement is possible, rotational spectroscopy can deliver a quantitative three dimensional structure of the molecule with correct stereochemistry as the analysis output. [1] David Patterson, Melanie Schnell, John M. Doyle, Nature 497, 475 (2013). [2] David Patterson, John M. Doyle, Phys. Rev. Lett. 111, 023008 (2013).

All rotationally resolved spectroscopic methods rely on sources of cold molecules. For the last three decades, the workhorse technique for producing highly supersaturated samples of cold molecules has been the pulsed supersonic jet. We present here progress on our alternative method, cryogenic buffer gas cooling. Our high density, continuous source, and low noise temperature allow us to record microwave spectra at unprecedented sensitivity, with a dynamic range in excess of 10⁶ achievable in a few minutes of integration time. This high sensitivity enables new protocols in both 1-D and 2-D microwave spectroscopy, including sensitive chiral analysis via nonlinear three wave mixing and applications as an analytical chemistry tool

Chiral epoxides built upon nominally rigid frameworks that incorporate aryl substituents have been shown to provide versatile backbones for asymmetric syntheses designed to generate novel pharmaceutical and catalytic agents. The ubiquity of these species has motivated the present studies of their intrinsic (solvent-free) circular birefringence (CB), the measurement of which serves as a benchmark for quantum-chemical predictions of non-resonant chiroptical behavior and as a beachhead for understanding the often-pronounced mediation of such properties by environmental perturbations (e.g., solvation). The optical rotatory dispersion (or wavelength-resolved CB) of (R)-styrene oxide (R-SO) and (S,S)-phenylpropylene oxide (S-PPO) have been interrogated under ambient solvated and isolated conditions, where the latter efforts exploited the ultrasensitive techniques of cavity ring-down polarimetry. Both of the targeted systems display marked solvation effects as evinced by changes the magnitude and (in the case of R-SO) the sign of the extracted specific optical rotation, with the anomalously large response evoked from S-PPO distinguishing it from other members of the epoxide family. Linear-response calculations of dispersive optical activity have been performed at both density-functional and coupled-cluster levels of theory to unravel the structural and electronic origins of experimental findings, thereby suggesting the possible involvement of hindered torsional motion along dihedral coordinates adjoining phenyl and epoxide moieties.

2,2,2-trifluoroethanol (TFE) is a common aqueous co-solvent in biological chemistry which may induce or destabilize secondary structures of proteins and polypeptides, thanks to its diverse intermolecular linkages originating from the hydrogen bonding potential of both the hydroxyl and perfluoro groups.M. Buck, Q. Rev. Biophys. 1998, 31, 297-335.heoretically, the TFE monomer is predicted to have two stable gauche (gauche⁺/gauche⁻) conformations whereas the trans form is unstable or is supported only by a very shallow potential. Only the gauche conformers have been identified in the gas phase, whereas liquid phase studies suggest a trans:gauche ratio of 2:3.I. Bakó, T. Radnai, M. Claire, B. Funel, J. Chem. Phys. 2004, 121, 12472-12480. he question at which sample (cluster) size the trans form of TFE would appear was one major motivation for our study.
Here, we report the detection of three trimers of TFE using Balle-Flygare cavity and chirped-pulse Fourier transform microwave spectroscopy (CP-FTMW) techniques. The most stable observed trimer features one trans- and two gauche-TFE subunits. The other two trimers, observed using a newly constructed 2-6 GHz CP-FTMW spectrometer, consist of only the two gauche conformers of TFE. Quantum Theory of Atoms in Molecules (QTAIM)R. F. W. Bader, Chem. Rev. 1991, 91, 893-928.nd non-covalent interactions (NCI)E. R. Johnson, S. Keinan, P. Mori-Sánchez, J. Contreras-Garcia, A. J. Cohen, W. Yang, J. Am. Chem. Soc., 2010, 132, 6498-6506.nalyses give detailed insights into which intermolecular interactions are at play to stabilize the trans form of TFE in the most stable trimer. M. Buck, Q. Rev. Biophys. 1998, 31, 297-335.T I. Bakó, T. Radnai, M. Claire, B. Funel, J. Chem. Phys. 2004, 121, 12472-12480. T R. F. W. Bader, Chem. Rev. 1991, 91, 893-928.a E. R. Johnson, S. Keinan, P. Mori-Sánchez, J. Contreras-Garcia, A. J. Cohen, W. Yang, J. Am. Chem. Soc., 2010, 132, 6498-6506.a

Vibrational Circular Dichroism (VCD), first discovered in the early 1970s, and commercialized in the late 1990's, is finally coming of age! No longer a curiosity of the few selected academic groups, it is now used by all major pharmaceutical companies, regulatory agencies, government labs and academic institutions. The main application for the technology has been determination of absolute configuration of small pharmaceutical molecules. In more recent years, this has extended to more complicated molecules such as natural products with many chiral centers and conformational flexibility. Other applications include determination of enantiomeric purity, chiral polymers, and characterization of other biological molecules such as proteins, carohydrates and nucleic acids. One of the most fascinating discoveries in the VCD field has been been unusual enhancement in intensity for proteins that form fibrils. We have demonstrated sensitivity of VCD to in situ solution-phase probe of the process of fibrillogenesis and subsequent development that currently can only be studied in detail with dried samples by such techniques as scanning electron microscopy or atomic force microscopy. We have further shown that several different proteins, that in their native state have different secondary structures, have a very similar unique signature of mature fibrils. In this presentation, we will discuss fundamentals of VCD, demonstrate a few examples of different applications and showcase the sensitivity to structure of fibrils, including new results on micro-sampling.

The conversion of enantiomeric molecules into spectroscopically distinct diasteromeric complexes has been proposed as a promising new means for chiral analysis. The success of this method requires the characterization of potential chiral tags as well as demonstrations of the feasibility and power of the technique. 2-(trifluoromethyl)- and 2-vinyloxirane are chiral molecules with simple, hyperfine-free spectra. They are high vapor pressure liquids that can easily be incorporated into a free jet expansion for complex formation and spectroscopic analysis, and they are commercially available in enantiomerically pure forms as well as racemic mixtures. The microwave spectra of these two molecules and their carbon and oxygen atom substitution structures are obtained as well as the spectrum and structure of the 2-(trifluoromethyl)-oxirane-argon complex.

Electronic circular birefringence (ECB), which causes rotation of the linear-polarization state for non-resonant light traversing an isotropic sample of chiral molecules, long has served as a robust means for assessing enantiomeric purity, but quantitative studies of this important property historically have been restricted to condensed phases where environmental effects (e.g., solvent-solute interactions or crystal-packing forces) can alter the magnitude and even the sign of the intrinsic behavior. As part of a continuing effort to elucidate the structural and electronic origins of such chiroptical phenomena, the dependence of optical rotatory dispersion (or wavelength-resolved ECB) on ring morphology has been explored for two saturated monocyclic amines, (R)-2-methylpyrrolidine and (S)-2-methylpiperidine. To assess the putative role of extrinsic perturbations, ambient measurements of specific optical rotation were performed under both solvated and isolated conditions, where the latter gas-phase work involved use of ultrasensitive cavity ring-down polarimetry. Each of the targeted compounds support active conformational degrees of freedom in the form of large-amplitude puckering motion of the heterocyclic ring combined with internal rotation of methyl substituents, with the antagonistic chiroptical properties exhibited by the resulting conformers combining to yield the overall response observed from a thermally equilibrated ensemble of molecules. Experimental ECB findings will be contrasted with those reported previously for ketones built upon comparable carbocyclic frameworks, and interpreted, in part, by reference to electronic-structure and linear-response calculations performed at various levels of quantum-chemical theory.

The absolute configuration of 3-methylcyclohexanone was established by chiral tag rotational spectroscopy measurements using 3-butyn-2-ol as the tag partner. This molecule was chosen because it is a benchmark measurement for vibrational circular dichroism (VCD). A comparison of the analysis approaches of chiral tag rotational spectroscopy and VCD will be presented. One important issue in chiral analysis by both methods is the conformational flexibility of the molecule being analyzed. The analysis of conformational composition of samples will be illustrated. In this case, the high spectral resolution of molecular rotational spectroscopy and potential for spectral simplification by conformational cooling in the pulsed jet expansion are advantages for chiral tag spectroscopy. The computational chemistry requirements for the two methods will also be discussed. In this case, the need to perform conformer searches for weakly bound complexes and to perform reasonably high level quantum chemistry geometry optimizations on these complexes makes the computational time requirements less favorable for chiral tag rotational spectroscopy. Finally, the issue of reliability of the determination of the absolute configuration will be considered. In this case, rotational spectroscopy offers a “gold standard” analysis method through the determination of the ¹³C-subsitution structure of the complex between 3-methylcyclohexanone and an enantiopure sample of the 3-butyn-2-ol tag.

The molecular interactions in complexes involving chiral molecules are of particular interest, because the interactions change in a subtle way upon replacing one of the partners by its mirror image. This is based on the fact that chiral molecules are sensitive probes for other chiral objects and chiral interactions. In this particular case, we will concentrate on molecule-molecule interactions and investigate them with broadband rotational spectroscopy. When two chiral molecules form complexes, the homochiral and heterochiral forms have different structures (and thus rotational constants and spectra) and different energies. They are diastereomers, which can easily be differentiated, for example via molecular spectroscopy. This is often exploited in chemical synthesis for identifying and separating enantiomers. The phenomena involving chirality recognition are relevant in the biosphere, in organic synthesis and in polymer design. We use chirped-pulse Fourier transform microwave (CP-FTMW) spectroscopy to study the structures and the underlying interactions of camphor-1,2-propanediol complexes. This system is also interesting because the complex formation can be expected to be ruled by an interplay between hydrogen bonding to the polar carbonyl group in camphor and dispersion interactions. The spectra are extremely rich because of the high number of conformers for 1,2-propanediol. We started out with racemic mixtures of both camphor and 1,2-propanediol. Using enantiopure samples of different handedness of the two partners nicely simplifies the spectra and guides the assignment. In the talk, we will report on the latest results for this chiral complex.

The microwave spectrum of the chiral molecule verbenone has been recorded from 2-18 GHz using two CP-FTMW spectrometers. 2-8 GHz data has been acquired on a 2-8 GHz CP-FTMW located at the University of Virginia and 8-18 data has been acquired on a 6-18 GHz spectrometer located at Missouri S&T. From the experiments the authors were able to assign and fit isotopologues corresponding to each heavy atom position (either ¹³C or ¹⁸O), providing for the heavy-atom structure. Previous studies by Evans and coworkers have been added to these measurements in a global fit of the parent species.C. J. Evans, S. M. Allpress, P. D. Godfrey, D. McNaughton, 67th International Symposium on Molecular Spectroscopy, 2012, RH13^, S. M. Allpress, Spectroscopic and Computational Chemistry Studies on Terpene Related Compounds, University of Leicester, 2015, Chapter 6: Microwave Spectroscopy of VerbenoneT